Article:Isocaloric Dietary Changes and Non-Alcoholic Fatty Liver Disease in High Cardiometabolic Risk Individuals. (5691682)

From ScienceSource
Jump to: navigation, search

This page is the ScienceSource HTML version of the scholarly article described at https://www.wikidata.org/wiki/Q47160560. Its title is Isocaloric Dietary Changes and Non-Alcoholic Fatty Liver Disease in High Cardiometabolic Risk Individuals. and the publication date was 2017-09-26. The initial author is Giuseppe Della Pepa.

Fuller metadata can be found in the Wikidata link, which lists all authors, and may have detailed items for some or all of them. There is further information on the article in the footer below. This page is a reference version, and is protected against editing.



Converted JATS paper:

Journal Information

Title: Nutrients

Isocaloric Dietary Changes and Non-Alcoholic Fatty Liver Disease in High Cardiometabolic Risk Individuals

  • Giuseppe Della Pepa
  • Claudia Vetrani
  • Gianluca Lombardi
  • Lutgarda Bozzetto
  • Giovanni Annuzzi
  • Angela Albarosa Rivellese

Department of Clinical Medicine and Surgery, Federico II University, 80131 Naples, Italy; gdp0206@libero.it (G.D.P.); c.vetrani@libero.it (C.V.); lombardi.gian@gmail.com (G.L.); lutgarda.bozzetto@unina.it (L.B.); annuzzi@unina.it (G.A.)

Publication date (epub): 9/2017

Publication date (collection): 10/2017

Abstract

Non-alcoholic fatty liver disease (NAFLD) incorporates an extensive spectrum of histologic liver abnormalities, varying from simple triglyceride accumulation in hepatocytes non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), and it is the most frequent chronic liver disease in the industrialized world. Beyond liver related complications such as cirrhosis and hepatocellular carcinoma, NAFLD is also an emerging risk factor for type 2 diabetes and cardiovascular disease. Currently, lifestyle intervention including strategies to reduce body weight and to increase regular physical activity represents the mainstay of NAFLD management. Total caloric intake plays a very important role in both the development and the treatment of NAFLD; however, apart from the caloric restriction alone, modifying the quality of the diet and modulating either the macro- or micronutrient composition can also markedly affect the clinical evolution of NAFLD, offering a more realistic and feasible treatment alternative. The aim of the present review is to summarize currently available evidence from randomized controlled trials on the effects of different nutrients including carbohydrates, lipids, protein and other dietary components, in isocaloric conditions, on NAFLD in people at high cardiometabolic risk. We also describe the plausible mechanisms by which different dietary components could modulate liver fat content.

Paper

1. Introduction

For its critical position between the systemic circulation and the blood flow of the gastrointestinal tract mediated by the portal vein, the liver plays an essential role in the intermediary metabolism, transforming dietary nutrients into the major chemical elements crucial for life and human health. Conversely, many nutrients and the overall dietary composition can influence liver function. In fact, an excessive intake of refined carbohydrate and saturated fats, the increased consumption of fructose and other simple sugars, and the progressive diffusion of high-calorie Western diets, the deleterious eating habits typical of the last forty years, have been associated with a dramatic increase in overweight/obesity and insulin resistance and, more recently, also with non-alcoholic fatty liver disease (NAFLD) [[1]]. Noteworthy, the excess of adiposity, in particular abdominal adiposity, and insulin resistance are the major contributors to the development of several cardiometabolic abnormalities strictly related to the increased risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Interestingly, NAFLD itself can be considered as an independent cardiometabolic risk factor beyond the classical cardiometabolic risk factors [[2]].

NAFLD is characterized by an excessive accumulation of lipids in the liver, primarily in the form of triglycerides, in the absence of a considerable alcohol ingestion (ethanol intake ≤ 30 g/day for men and ≤20 g/day for women), and ruling out other causes of liver injury [[3]]. The term NAFLD incorporates an extensive spectrum of histologic liver abnormalities, varying from simple triglyceride accumulation in hepatocytes non-alcoholic fatty liver (NAFL) or steatosis to non-alcoholic steatohepatitis (NASH), characterized by the additional presence of inflammation and tissue injury [[4]].

1.1. NAFLD and Cardiometabolic Risk

NAFLD is the most common chronic liver disease in the industrialized world with a 15–30% prevalence reported in the general population [[5]]. In particular, the prevalence of NAFLD is very high in individuals at high cardiometabolic risk. Cardiometabolic risk refers to a condition strongly associated with an increased risk of developing CVD and T2DM as a consequence of the presence of interrelated alterations in metabolic and vascular functions, as well as of dyslipidemia, hypertension, abdominal obesity, insulin resistance and hyperglycemia. All these abnormalities identify the metabolic syndrome; consequently, the close association between NAFLD and metabolic syndrome is unsurprising [[6],[7]]. In line with these observations, the prevalence of NAFLD is approximately 50% in hypertensive subjects, 70% in people with T2DM, and up to 90% in severely obese patients [[8],[9],[10]]. Dramatically, NAFLD is also the most prevalent form of chronic liver disease in childhood and very recent data indicate that nearly 70–80% of obese children may have NAFLD [[11]]. Given the increasing prevalence of obesity and metabolic syndrome, NAFLD will become one of the most important public health challenges in the next decades for its related complications. In particular, it should be considered that simple NAFLD can progress to NASH in about 20–25% of cases, and nearly 20% of patients with NASH can develop fibrosis and cirrhosis [[12]]; in patients with cirrhosis, the cumulative incidence of hepatocellular carcinoma ranges from 2.4% to 12.8% over 3–7 years [[13]]. Beyond the liver-related complications, it is important to underline that NAFLD is also an emerging risk factor for T2DM and CVD [[14],[15]], and that it has recently been associated with an increased risk of chronic kidney disease [[16]].

1.2. Pathogenesis of NAFLD

The mechanisms involved in NAFLD development and progression are not completely clear. The hypothesis of the “two-hit” model for the first time proposed by Day et al. in 1998 in the pathogenesis of NAFLD has been accepted for about one decade [[17]]. According to this model, the “first hit” is characterized by the accumulation of lipids primarily in the form of triglycerides derived from esterification of free fatty acids and glycerol in the hepatocytes. [[18]]. In particular, Donelly et al. clearly observed that 59% of the triglycerides present in the liver of patients with NAFLD derived from free fatty acids released from adipose tissue, 26% from de novo lipogenesis, and 15% from dietary lipids [[19]]. The low rate of β-oxidation of free fatty acids and the reduction in triglyceride export by very low density lipoprotein particles in a liver with increased fat content is also important [[20]]. Insulin resistance plays a pivotal role in the “first-hit” and in liver triglyceride accumulation. Increasing the free fatty acids release from adipose tissue, reducing the glucose uptake from the skeletal muscle and favoring the hepatic influx of these metabolites; furthermore, insulin resistance increases de novo lipogenesis and reduces the synthesis and secretion of very low density lipoprotein [[21]].

The increase in liver triglyceride content is strongly associated with hepatocyte susceptibility to the damage promoted by the “second hit”. The “second-hit” can be promoted by lipid peroxidation, oxidative stress, inflammatory cytokines, and mitochondrial dysfunction. All together, these factors induce steatohepatitis and can lead to fibrosis, which can evolve into cirrhosis [[22]].

In the last few years, based on a large body of knowledge, the hypothesis of the “two-hit” model has been translated into the “multiple-hit” model. In fact, it appears reasonable that the simple “two hit” mechanism is too reductive and inadequate to explain the complex mechanisms involved in NAFLD development and progression; furthermore, only a minority of patients with NAFLD progress to NASH or cirrhosis [[1]], and, on the other hand, steatohepatitis can precede simple steatosis [[23]].

The “multiple-hit” model provides a comprehensive model that takes into account the multiple factors and interactions involved in NAFLD [[24]]. Based on this model, dietary habits, insulin resistance, visceral adiposity, inflammatory state, oxidative stress, alteration in microbiome, and genetic predisposition, are all recognized risk factors for NAFLD development and progression.

In particular, the type of diet, other environmental factors and genetic predisposition play an important role in the development of insulin resistance, visceral obesity, and gut microbiome changes. Insulin resistance promotes steatosis with the mechanisms above discussed; adipose tissue is involved beyond the free fatty acids efflux in the production and secretion of the inflammatory cytokines and adipokines involved in NAFLD progression [[25]]. Changes in the gut microbiome related to dietary habits can influence energy homeostasis and systemic inflammation [[24]]; all these factors can aggravate oxidative stress and endoplasmic reticulum stress in hepatocytes, leading to hepatic inflammation [[26]]. Furthermore, genetic predisposition of single nucleotide polymorphisms in genes such as Patatin-Like Phospholipase 3 (PNPLA3) or in Transmembrane 6 Superfamily Member 2 (TM6SF2) can aggravate liver injury [[27]] (Figure 1).

With respect to the strong relation between genetic predisposition and dietary habits, NAFLD represents an optimal example of disease by which nutrigenomics has allowed us to understand how nutrients can influence its development and progression by altering the expression of genes involved in inflammation, glucose and lipid metabolism [[28]]. Nutrigenomics focuses on identifying and understanding molecular interactions between nutrients/dietary bioactive compounds with the genome [[29]]. With regard to NAFLD, the PNPLA3 I148M polymorphism is a clear example of these possible interactions: individuals with the PNPLA3 I148M polymorphism are more prone to develop steatosis when the intake of carbohydrates, in particular simple sugars, is elevated [[30]]. Briefly, PNPLA3 exerts a lipolytic activity on triglycerides and its up-regulation is mediated by carbohydrates [[31]]; in individuals with the PNPLA3 I148M polymorphism, the high intake of carbohydrates induces the accumulation of the pathological protein less able to hydrolyze the triglycerides on the surface of lipid droplets and a consequent decreased secretion of triglyceride-rich lipoproteins from the liver [[32]]. Based on these observations, individualized nutritional strategy considering also the genetic features of individuals may be more effective in clinical management of NAFLD.

1.3. Diagnosis of NAFLD

Liver biopsy is still the gold standard for the diagnosis of NAFLD, and this invasive procedure despite some limitation related to sampling variability and procedural potential risk discerns simple NAFL from NASH [[33]]. However, in large population assessment or for disease monitoring, some non-invasive markers have been proposed. In terms of biochemical markers, it should be considered that serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are inaccurate markers of NAFLD [[33]].

For NAFL evaluation the best validated scores are represented by: the fatty liver index [[34]], the NAFLD liver fat score [[35]] and the Steato test [[36]], based on some biochemical markers and clinical parameters. In terms of instrumental evaluation, the first-step is represented by ultrasonography (US) [[37],[38]], although it is limited by the possible interference of liver fibrosis on bright liver echo pattern and the very low sensitivity and specificity in individuals with BMI > 40 kg/m2. CT presents similar accuracy for NAFLD as US; however, it is limited by radiation exposure [[33]]. The proton magnetic resonance spectroscopy (1H-MRS) can reveal a liver fat content as low as 1%, but it is limited by its high cost [[33]]. In terms of biochemical markers, cytokeratin-18 (CK-18) fragments, derived from hepatocytes apoptosis or death, are only modestly accurate; therefore, for the diagnosis of NASH, liver biopsy is still the only diagnostic procedure [[39]]. Several scores based on biochemical parameters have been proposed to evaluate liver fibrosis as NAFLD Fibrosis Score, Fibrosis 4 Calculator, Enhanced Liver Fibrosis, and the Fibro Test [[40]]. Transient elastography is the instrumental imaging performed for the evaluation of liver fibrosis, but it has a high rate of false positive results [[41]].

1.4. Management of NAFLD: Hypocaloric Diet and Physical Activity

At present, lifestyle intervention including strategies to reduce body weight and increase regular physical activity represents the mainstay of NAFLD management. Recently, the Clinical Practice Guidelines for the management of NAFLD proposed by a joint effort of the European Association for the Study of the Liver, the European Association for the Study of Obesity, and the European Association for the Study of Diabetes recommended a 7–10% body weight loss in overweight/obese patients with NAFLD as a target to achieve [[33],[42]]. A similar target is proposed by the American Association for the Study of Liver Diseases [[2]].

Body weight loss in NAFLD can be achieved by hypocaloric diet alone or in combination with increased physical activity.

Although total calorie intake plays a very important role in both the development and the treatment of NAFLD, only modulating the quality of the diet, i.e., changing either the macro or the micronutrient composition, can also markedly affect the clinical evolution of NAFLD offering a more realistic and feasible treatment alternative. To this regard, the Mediterranean diet characterized by high consumption of olive oil as source of added fat, legumes, whole grains, fruits, vegetables, and fish; a low consumption of dairy products and meat; and a moderate alcohol assumption [[43]] could represent an adequate therapeutic approach in NAFLD prevention and treatment and this dietary pattern has been recently recommended as good for the management of NAFLD [[33]].

The beneficial effect of Mediterranean diet on many metabolic chronic disease is largely supported by several epidemiological studies [[44]]. To date, some observational studies and few clinical trials have investigated the effects of Mediterranean diet on NAFLD; recently, Zelber-Sagi et al. have comprehensively reviewed the evidence on this aspect [[45]]. Nine studies are reported by the authors three cross sectional studies, one case-control study and five intervention trials and the adherence to the Mediterranean diet was significantly related to an improvement of NAFLD specific outcomes evaluated, i.e., reduction in liver enzymes in one study, reduction in liver fat content evaluated by 1H-MRS in three studies and by US in two studies, reduction in the fatty liver index in one study, and a lower grade of steatosis in the two studies a cross-sectional and a case-control, respectively, in which liver biopsy was performed [[45]].

The aim of the present review is to summarize the current evidence available on the effects of different nutrients, lipids, carbohydrates, protein and other dietary components on NAFLD in people at high cardiometabolic risk, in particular individuals with abdominal obesity and other metabolic abnormalities as well as dyslipidemia, hypertension, and hyperglycemia.

We have comprehensively evaluated the evidence from randomized controlled trials performed in humans to study the effects of different dietary components on NAFLD considering biochemical markers, liver scores, liver imaging US, 1H-MRS or computed tomography (CT) or liver biopsy as possible outcomes. It is important to underline that we have reported and discussed only trials evaluating the effects of nutrients in isocaloric conditions, i.e., the dietary regimen was designed to be neutral in energy balance compared with control. For n-3 polyunsaturated fatty acids (PUFA), vitamins and other bioactive dietary components, randomized controlled trials with dietary supplementation were considered. We also describe the plausible mechanisms by which different dietary components could modulate liver fat content.

2. Diet Composition and Non-Alcoholic Fatty Liver Disease in Isocaloric Conditions

2.1. Dietary Fatty Acids

In NAFLD as well as in other conditions (insulin resistance, blood lipids, etc.), the quality of different fatty acids seems to be more important than the total amount. Therefore, we will consider the different types of dietary fat separately.

2.1.1. Saturated Fatty Acids

Saturated fatty acids (SFA) contain no double bonds in the straight-chain hydrocarbon with varying length ranging from short chain length (volatile liquids) to chain lengths of 30 or more carbon atoms (waxy solids). The main food sources are animal fat products such as cream, cheese, butter, other whole milk dairy products and fatty meats and eggs, but also some vegetable fat, i.e., coconut and palm kernel oils. The most consumed SFA are myristic (C14:0), palmitic (C16:0) and stearic (C18:0) acids.

Observational studies focusing on dietary habits of patients with NASH have suggested the possible negative influence of SFA, since their diets were richer in SFA than in other fatty acids compared to subjects with simple liver steatosis [[46]] or to the general population [[47]].

Along this line, controlled intervention studies demonstrated that increasing dietary SFA in isocaloric substitution of carbohydrates [[48]] or PUFA [[49]] increased hepatic and visceral fat accumulation in healthy subjects.

The detrimental effect of SFA on liver fat may be mediated by the increase in insulin resistance and oxidative stress, both associated with NAFLD. To date, studies in vitro and in animal models have shown that SFA could induce lipogenesis by promoting the transcription of peroxisome proliferator-activated receptor-gamma (PPAR-γ) coactivator-1β and the sterol regulatory element-binding transcription factor 1c (SREBP-1c). In addition, they promote oxidative stress, and apoptosis of hepatocytes [[50],[51]], possibly leading to the progression of NAFLD to NASH [[52]].

2.1.2. Monounsaturated Fatty Acids and n-6 Polyunsaturated Fatty Acids

Monounsaturated fatty acids (MUFA) contain one double bond in their aliphatic hydrocarbon chain. MUFA are mainly found in plant-based foods such as olive oil, canola oil, nuts, soy and avocado, and to a lesser extent in red meat and whole milk products. The greatest source of dietary MUFA (~90% of all MUFA) is oleic acid (C18:1 n9), followed by palmitoleic acid (C16:1 n9).

PUFA contain more than one double bond in their chemical structure. There are two main PUFA groups with relevant biological functions and they are classified by the position of their first double bond counting from the methyl carbon: n-6 PUFA with their first unsaturated bond at carbon6 and n-3 PUFA at carbon 3. The most biologically relevant n-6 PUFA are linoleic acid (LA, 18:2) and arachidonic acid (AA, 20:4); their main dietary sources are flaxseed and some nuts.

Albeit scant, the evidence available to date shows quite clearly the effectiveness of MUFA on liver fat (Table 1). After an eight-week intervention with a high-MUFA diet (28% of total energy) vs. a high-carbohydrate/high-fiber/low-glycemic index diet (MUFA 16% of total energy), a 29% reduction of liver fat content, measured by 1H-MRS, was observed in a group of T2DM subjects without body weight changes in comparison to a baseline diet moderately rich in SFA (13% of total energy) [[53]].

An even greater reduction (−39%) was observed in only six weeks by Ryan and colleagues [[54]] in a group of T2DM subjects with NAFLD. The participants were assigned to an isocaloric Mediterranean diet (MUFA intake 23% of total energy) where the main MUFA sources were extra-virgin olive oil, olives and nuts, whereas the control diet was a low-fat/high-carbohydrate diet (MUFA intake 8% of total fat). In a long-term intervention trial (24 weeks) [[55]], olive oil (MUFA 70%) and canola oil (MUFA 61%) consumption was compared to control oil (soybean or safflower oil such as the most common oil used in the habitual diet, MUFA 15–24%) in a group of Indian men. The two active groups showed a remarkable reduction of fatty liver grading evaluated by US, with 66.7% and 76.7% of the participants in the olive and canola oil groups, respectively, reverting to normal liver grading after the intervention.

Although the evidence is rather convincing, the exact mechanism through which MUFA could affect hepatic triglycerides content is not completely clear. In both in vitro and in vivo studies, MUFA have been shown to activate peroxisome proliferator-activated receptor-alfa (PPARα) and PPARγ [[56]], increasing lipid oxidation [[57],[58],[59]] and inhibiting lipogenesis [[58],[60]], thus leading to a reduction in hepatic steatosis (Figure 2). On the other hand, MUFA can promote fatty acid deposition in adipose tissue rather than in the liver, enhancing the clearance of circulating triglyceride rich lipoproteins by lipoprotein lipase [[61]]. In addition, clinical studies suggest that the beneficial effects of MUFA on NAFLD may be driven also by an improvement in blood lipid profile (reduction of triglycerides, VLDL, LDL and oxidized-LDL, and an increase in HDL), insulin resistance and obesity-related inflammation [[62],[63]].

As for the effect of n-6 PUFA on NAFLD, only one study met our inclusion criteria (Table 1). In a 10-week isocaloric randomized and controlled trial [[64]], participants were assigned either a PUFA diet or a saturated fat diet. Fat quality difference was obtained by the selection of specific foods: sunflower oil and seeds for the PUFA diet (linoleic acid 15%), and butter for the saturated fat diet group. After the intervention, liver steatosis assessed by 1H-MRS was significantly reduced with the PUFA diet compared to the SFA diet (−26% vs. +8%, respectively). In this study as well as in other studies with MUFA, no effects on liver enzymes were observed and no liver biopsies were performed.

Therefore, we can conclude that MUFA and n-6 PUFA seem to have beneficial effects on liver fat content in individuals at high cardiometabolic risk.

As for the possible mechanisms, PUFA are key regulators of the transcription of genes associated with lipid metabolism and mitochondrial β-oxidation (i.e., PPAR-α and SREBP-1). Thus, increasing PUFA intake may lead to a reduction of lipogenesis in favor of an increased hepatic fatty oxidation [[65]] (Figure 2).

2.1.3. n-3 Polyunsaturated Fatty Acids

As reported above, n-3 PUFA is one of the two main PUFA groups with relevant biological functions. The most biologically relevant n-3 PUFA are α-linolenic acid (ALA, 18:3), eicosapentaenoic acid (EPA, 19:5) and docosahexaenoic acid (DHA, 22:6). The main dietary sources of n-3 PUFA are fish oil, flaxseed and some nuts; however, DHA and EPA are synthetized from ALA. Several studies on n-3 PUFA supplementation and NAFLD are available in individuals at high cardiometabolic risk. Overall, the available evidence still produces conflicting results (Table 2).

In a 24-week intervention trial, a complete fatty liver regression was observed after a 2 g/day of n-3 PUFA supplementation in the context of an American Heart Association (AHA) diet in 33.4% of the patients. The daily energy intake of the ADA diet was composed of 50% carbohydrates, 20% protein and 30% fat, and an eating pattern including a variety of fruits and vegetables, whole grain products, fat-free and low-fat dairy products, fish, peas, poultry and lean meats was recommended [[66]]. Interestingly, there was a significant improvement in the echogenicity score in the whole active group (AHA diet +2 g/day n-3 PUFA) as compared with the control group (AHA diet alone), the former displaying also a decrease in ALT concentration. These findings were further confirmed by the results of the WELCOME study [[67]]. The supplementation with 4 g/day of PUFA (1 g containing 460 mg of EPA and 380 mg of DHA) over 18 months significantly affected liver fat content in a dose-dependent manner (1% DHA enrichment in erythrocytes was associated with a 3% reduction in liver fat percentage) as compared with placebo.

Increasing the amount of n-3 PUFA to 6 g/day in the context of an AHA diet, Zhu et al. [[68]] detected a full reversion of liver steatosis in 19.7% of their patients, and an overall improvement of fatty liver grading in 53% of the study population after a 24-week intervention with no adverse events in patients who completed the treatment. In addition, ALT decreased more significantly in the treatment group than in the placebo group.

In contrast with the above studies, an eight-week supplementation with 9 g/day of fish oil (51.4% EPA and 23.9% DHA) vs. placebo did not affect hepatic triglyceride content measured by 1H-MRS [[69]]; similarly, Argo et al. [[70]] did not detect any improvement of fatty liver or inflammation, ballooning, or fibrosis scores in a group of subjects receiving 3 g/day of fish oil (35% of EPA and 25% of DHA) for 12 months as compared with the placebo group. On the same line, a 12-month supplementation with EPA (1.8 mg/day or 2.7 g/day) had no significant effects on the key features of NASH (i.e., fibrosis, lobular inflammation, and hepatocyte ballooning) [[71]].

Cussons and colleagues [[72]] compared the effects of the daily consumption of n-3 PUFA or MUFA in a group of women with polycystic ovary syndrome, a condition associated with NAFLD. According to an eight-week crossover randomized and controlled trial, they consumed 4 g/day of n-3 PUFA (56% DHA and 27% EPA) and a placebo (4 g/day, 67% oleic acid). Both arms reduced liver fat measured by hepatic 1H-MRS (n-3 PUFA: 18.2% vs. MUFA: 14.8%).

As reported above, the effectiveness of n-3 PUFA supplementation on liver fat content is still controversial. This lack of concordance may be due, at least in part, to the largely different doses used in the trials (ranging from 0.25 to 6 g/day), the length of the exposure (from 2 to 18 months), and finally the imaging methods (US vs. 1H-MRS). Nevertheless, the only two studies looking at NASH features on liver biopsies showed no effect of n-3 PUFA.

To date, evidence of the mechanisms linking n-3 PUFA supplementation and NAFLD derives mainly from in vitro and animal studies. First of all, as reported for n-6 PUFA, increasing PUFA intake may increase fatty oxidation in the liver through the modulation of PPAR-α and SREBP-1 [[65]]. On the other hand, EPA and DHA are important modulators of the inflammatory pathway and, consequently, may inhibit pro-inflammatory eicosanoid production by inflammatory cells related to hepatic injury in NAFLD (Figure 2).

2.2. Carbohydrates

In the last few years, clear evidence has emerged that carbohydrates quality is more important than quantity in determining metabolic effects, and this seems particularly relevant for the possible effect on liver fat. Therefore, we evaluate the effects of the quality of carbohydrates on liver fat especially in terms of glycemic index (GI) and simple sugars.

2.2.1. Low Glycemic-Index Carbohydrate and Fiber Rich Diets

The association among high carbohydrate intake, high GI carbohydrate consumption, insulin resistance and liver fat accumulation has been found in animal models and observational studies [[73],[74]]. In particular, in a cross-sectional study, the prevalence of high-grade liver steatosis increased significantly across quartiles of high GI versus low GI diets [[75]]. In fact, available carbohydrates produce an increase in serum levels of glucose that can be used for the synthesis of new triglycerides through de novo lipogenesis in the liver [[76]]. The consumption of foods with high GI promotes insulin resistance, a condition strongly related to NAFLD [[77]], and the negative effect of a high GI diet on liver fat content can be observed in few days [[78]]. Conversely, low GI meals could have beneficial effect on NAFLD. In fact, low GI foods, especially foods rich in fiber, can decrease glucose absorption, reducing hepatic influx of glucose and de novo lipogenesis [[79]]; in addition, the fiber content of low GI foods can positively act on the gut microbiome, a possible mediator by which nutrients may influence liver fat content [[80]] (Figure 2).

Although GI seems to be an important factor in NAFLD prevention and treatment, few clinical trials have investigated the effect of low GI or low glycemic load (GL) at isocaloric conditions on NAFLD in patients at high cardiometabolic risk (Table 3).

It is important to underline that, in all of the above studies, the diets utilized were different not only for GI but also for other dietary components which could influence per se the parameters evaluated. Three studies evaluated the effects of low GI diets on liver fat compared to diets with higher GI, and two of them found a significant reduction in liver fat evaluated by 1H-MRS in one and by US in the other [[81],[82]]; no change was observed in the third study performed in obese children [[83]]. In none of these three studies was there any change with respect to liver enzymes; on the other hand, a reduction in ALT was reported after a low GI diet and a Mediterranean diet compared to a control diet in one intervention trial performed in patients with T2DM in which only liver enzymes were analyzed [[84]].

The fiber content of foods is one of the most important factors related to GI. Dietary fiber is defined as a non-digestible food ingredient; based on solubility it can by classified into soluble pectins, fructans, oligosaccharides and gums and insoluble hemicellulose, cellulose and lignin, and it is widely found in fruits, vegetable, whole grains and legumes [[85]]. Some epidemiological studies have shown that fiber intake in NAFLD patients is lower than in healthy individuals [[86],[87],[88]].

However, if we exclude the trials in which fiber was part of multifactorial dietary changes, only limited research regarding the effects of fiber alone on NAFLD has been done. We have found only one study evaluating the effects of a non-digestible carbohydrate, oligofructose (Table 3). In this trial, a decrease in ALT and AST was found after 16 g of oligofructose compared to maltodextrine in patients with NASH although no change in liver fat was detected at US [[89]].

Trying to draw some conclusions from the trials evaluating the effects of low GI diets on NAFLD, the few data available indicate that the low GI may have some role within the context of a diet characterized by other favorable changes such as, in primis, the reduction of saturated fatty acids.

2.2.2. Fructose/Other Simple Sugars

The intake of simple sugars increases liver fat content in animal models [[90],[91]] and epidemiological studies suggest an association between consumption of soft drinks and NAFLD development in humans [[92],[93],[94]].

Simple sugars, in particular fructose, has been shown to promote hepatic lipogenesis by stimulating SREBP-1c and carbohydrate response element-binding protein (ChREBP), the major transcription factors of many enzymes involved in de novo lipogenesis [[95],[96],[97]]. Furthermore, it has been observed that fructose and glucose consumption in addition to stimulating SREBP-1c and ChREBP may produce inflammation and activate cellular stress pathways [[98],[99]] (Figure 2).

Many clinic trials have investigated the effect of simple sugars mainly fructose, glucose and sucrose on NAFLD in healthy individuals and in those at high cardiometabolic risk [[100],[101],[102],[103],[104],[105],[106],[107]], and two meta-analyses on this issue were carried out [[108],[109]]. Briefly, the first meta-analysis reported that, in healthy subjects, using high doses of fructose in terms of 104–220 g/day in a hypercaloric diet increased both liver fat content and serum ALT levels, while it did not produce any effect in isocaloric conditions [[108]]. Similar findings were reported by the second meta-analysis where it was observed that the excess of added sugar intake in a hypercaloric diet compared with a eucaloric control diet increased liver fat content [[109]].

Only three trials have looked specifically at the effect of simple sugars intake as part of an isocaloric diet in overweight/obese subjects (Table 3).

Johnston et al. investigated the effects of glucose- or fructose-sweetened beverages providing 25% of energy requirements during an isocaloric period of two weeks. At the end of treatment, in overweight patients with NAFLD, serum ALT and AST levels, and liver fat content evaluated by 1H-MRS were unchanged [[110]]. Similar findings were reported by Bravo et al. who investigated the effects of three different levels of sucrose or high-fructose corn syrup (55% fructose) at 8%, 18%, or 30% of the calories required for weight maintenance in overweight patients with NAFLD. At the end of a 10-week intervention, liver fat content evaluated by CT was unchanged [[103]]. On the other hand, Maersk et al. compared the effects of four different drinks 1 L/day of regular cola, or isocaloric semi-skim milk, or aspartame-sweetened diet cola or water in obese subjects with NAFLD. After 24 weeks of treatment, drinking regular cola resulted in a higher amount of liver fat content, evaluated by 1H-MRS. In particular, in pairwise comparisons, the increment was 143% compared with milk, 139% compared with diet cola, and 132% compared with water, despite the fact that total energy intake was not different between groups during the study, indicating that the consumption of regular cola and milk was compensated for by reducing the energy intake from other sources [[102]].

In conclusion, even if data are still limited, it seems that simple sugars, at least within the context of an isocaloric diet, do not have a marked deleterious influence on liver fat in overweight individuals, while frankly obese subjects may be more sensitive to the exposure to simple sugars even within an isocaloric diet.

2.3. Proteins

Limited evidence on the effect of proteins on NAFLD is available. In animal models, a reduction in liver fat content was observed when protein intake was increased [[111]].

A very recent analysis of The Rotterdam Study, a large epidemiological study, showed that total protein intake, in particular proteins of animal origin, was associated with higher odds of NAFLD in overweight subjects (OR = 1.50; 95% CI 1.17–1.92) [[112]]; similarly, a cross-sectional evaluation of the Israeli National Health and Nutrition Survey showed that the intake of meat was significantly associated with an increased risk for NAFLD (OR = 1.37, 95% CI 1.04–1.83) [[113]].

The effect of protein intake on NAFLD has been evaluated only in few controlled clinical trials, generally adopting hypocaloric diets [[114],[115],[116]]. Therefore, it is not possible to draw any conclusion about the possible effect of proteins per se on NAFLD.

2.4. Other Dietary Components

2.4.1. Polyphenols

Polyphenols represent a great variety of secondary plant metabolites and, based on their chemical structure, they can be divided into two major categories: flavonoid and non-flavonoids. About 8000 phenolic compounds in the plant kingdom have been discovered. Vegetables, cereal grain, fruits, and some beverages—tea, coffee, red wine, and beer—are good sources of polyphenols [[117]]. Mean total dietary intake of polyphenols was 1193 ± 510 mg/day in a French cohort [[118]]. These natural compounds are powerful antioxidants, in addition to having many other properties such as anti-inflammatory, anti-mutagenic, and immunomodulatory activities [[117]].

Phenolic compounds have received growing interest over the last few years and epidemiological studies have shown an inverse correlation between high polyphenol consumption and incidence of many chronic metabolic diseases, including obesity, insulin resistance, and CVD [[119]]. A randomized controlled trial in individuals at high cardiometabolic risk showed that diets naturally rich in polyphenols improved fasting and postprandial dyslipidemia and reduced oxidative stress [[120]]. Recently, beneficial effects of polyphenols on NAFLD have been reported in animal models [[121]].

Polyphenols could prevent liver fat accumulation and NAFLD progression through several mechanisms. In both in vitro and animal models, it has been observed that polyphenols may reduce hepatic lipogenesis and increase free fatty acid oxidation. In particular, polyphenols can decrease the transcription of SREBP-1c [[122]] and increase transcription of PPAR-α. Moreover, polyphenols can improve insulin sensitivity and reduce the transcription of inflammatory cytokines [[123],[124],[125]]. All these molecular pathways can be indirectly modulated by the effect of polyphenols on the activation of AMP-activated protein kinase [[126]]. Finally, the antioxidant properties of phenolic compounds in reducing oxidative stress involved in NAFLD progression should be also considered [[121]] (Figure 2). Whereas from these animal and in vitro studies it can be argued that polyphenols may have positive influence on different aspects of NAFLD, the controlled intervention trials in humans have produced discordant results (Table 4).

The effects of mixed phenolic compounds have been investigated by two trials [[127],[128]]. Chang et al. [[127]] evaluated in overweight NAFLD patients the effects of 150 mg/day of polyphenols composed of 1.43% flavonoids, 2.5% anthocyanins and 1.7% phenolic acids compared to placebo. After 12 weeks of treatment, in the polyphenol group a significant 15% reduction in fatty liver score was observed, with no changes in AST or ALT levels. In this group, a decrease in body weight, BMI, body fat and waist-to-hip ratio was also observed, possibly accounting, at least in part, for the reduction in fatty liver score. In a trial conducted by Guo et al. [[128]], young NAFLD patients evaluated by US were given 250 mL of bayberry juice or placebo twice daily for four weeks. The amount of polyphenols—anthocyanins and phenolic acids—was 1350 mg/day. No significant differences in the serum levels of AST and ALT between the groups were observed; however, a reduction in serum levels of hepatocytes apoptosis biomarkers, namely CK-18 and tissue polypeptide-specific antigen, was reported.

Two more trials evaluated the effects of specific polyphenols, anthocyanins and catechins, respectively [[129],[130]]. In the first one, overweight NAFLD men were assigned to consume two bottles of purple sweet potato beverage or placebo. The amount of phenolic compounds represented by acylated anthocyanins was 400 mg/day. After eight weeks, the intake of purple sweet potato beverage induced a significant reduction in the serum levels of ALT versus placebo [[129]]. In the second study, Sakata et al. [[130]] investigated the effects of green tea with high-density catechins in overweight NAFLD patients evaluated with ultrasonography and computed tomography. Patients were randomized to consume different amounts of catechins, 0, 200, or 1080 mg/day, for 12 weeks in a cup of 700 mL/day. The consumption of the highest dose of catechins significantly decreased serum ALT level by 42.1% and improved liver fat content with a liver-to-spleen CT attenuation ratio that increased from 92% to 102%.

Resveratrol is currently one of the more studied polyphenols, and five trials have been conducted on NAFLD. In two of these studies, resveratrol at the dose of 500 mg/day and 1500 mg/day, respectively, did not induce any change in the different liver outcomes evaluated (liver fat content by imaging, liver markers, histological changes) [[131],[132]]. In another intervention trial, where a higher dose of resveratrol was used 3000 mg/day a transient increase in ALT and AST was observed at Week 6, with no change at the end of the intervention in liver enzymes or in liver fat [[133]]; conversely, two trials showed some beneficial effects [[123],[134]]. Chen et al. [[123]] observed a significant reduction in serum ALT and AST, fibroblast growth factor-21 and CK-18 after three months of treatment with 600 mg/day of resveratrol versus placebo, while no significant differences in hepatic fat content was found. Similarly, Faghihzadeh et al. [[134]] evaluated the effects of 500 mg/day of resveratrol versus placebo in overweight patients for 12 weeks. After the intervention period, serum levels of ALT and AST were significantly decreased in both groups, although in patients on resveratrol a significantly greater reduction in ALT (−32.3%, p = 0.03) was found. Furthermore, in the resveratrol group a significant reduction in CK-18 was observed as well as an improvement in the hepatic tissue echogenicity. Nevertheless, the transient elastography did not show a reduction in hepatic fibrosis grade.

Therefore, based on these data, catechins and antocianins seem to have some beneficial influence on liver fat, but this needs to be corroborated by additional evidence. As for resveratrol, the results are so discordant that no definite conclusion can be drawn.

2.4.2. Caffeine

Caffeine, an alkaloid xanthine derivate, represents the main compound of coffee, the most consumed beverage worldwide, and can also be found in some food, tea and soft drinks.

Over the last few years, epidemiological studies have shown an inverse correlation between high coffee or caffeine consumption and incidence of many chronic metabolic diseases, even if many studies have been unable to evidence if the beneficial effect is related to coffee or caffeine [[135]]. In several prospective and cross sectional studies, the relationship between coffee/caffeine consumption and NAFLD has been investigated and we report the comprehensive results of three meta-analyses published in the last year [[136],[137],[138]]. It should be considered that controlled clinical trials have not been performed so far.

Wijarnpreecha et al. reported a 29% significant reduction in the risk of developing NAFLD in patients who drank coffee (RR, 0.71; 95% CI, 0.60–0.85) and a 30% decreased risk of developing liver fibrosis [[136]]. Marventano et al. reported an inverse association of caffeine intake with fibrosis levels in four of seven studies on NAFLD fibrosis [[137]], while Shen et al. reported that only regular coffee/caffeine intake, i.e., ingestion of caffeine only from regular coffee, not including other caffeinated beverages such as soda, tea, espresso, etc., was significantly associated with reduced hepatic fibrosis in two out of three studies also analyzed by Marventano [[138]]. In conclusion, most of the evidence on coffee/caffeine and NAFLD suggest that coffee more than caffeine may have beneficial effect on fibrosis, however, it should be considered some limitations of these studies: the definition of regular coffee consumption widely varied between studies; furthermore, these are meta-analyses of observational studies that could only show an association, but not a causal relationship. With respect to the plausible mechanisms, it has been reported that caffeine may reduce the progression of liver fibrosis by inhibiting hepatic stellate cell adhesion and activation [[139]]. Furthermore, it is important to underline that other coffee compounds present in coffee such as polyphenols and melanoidins could positively influence NAFLD [[140]].

2.4.3. Vitamin E

The term vitamin E refers to eight lipid-soluble compounds four tocotrienols and four tocophenols with powerful antioxidant properties. These essential vitamins are synthesized in vegetables and are largely present in seeds, nuts, vegetable oils, green leafy vegetables and fortified cereals [[141]]. In terms of vitamin E pharmacokinetics it is important to underline that all the eight isoforms reach the liver, but only the α-tocopherol form for the selective binding offered by the α-tocopherol transfer protein is retained at high levels in hepatocytes, whereas other vitamin E forms are preferentially metabolized by microsomal P450 or excreted into the bile [[142]].

Vitamin E plays a key role in many physiological functions: it is one of the most powerful antioxidant and acts as free radical scavenger; it is also involved in the regulation of platelet aggregation, protein kinase C activation, immune function, gene expression, and other metabolic processes [[143]].

Oxidative stress and inflammation are the major contributors to NAFLD progression, and vitamin E could play an important role in mitigating oxidative stress. Vitamin E could avoid the progression of NAFLD and improve NASH by virtue of its antioxidant capacity and as free radical scavenger. It has been observed that vitamin E reduces the inflammatory pathway in NASH by several mechanisms, beyond its “simple” antioxidant activity; in particular, vitamin E could improve superoxide dismutase activity and could decrease the transcription of many genes related to inflammation and liver fibrosis [[144],[145],[146],[147]]; it has been also reported that vitamin E could improve insulin sensitivity [[148]] (Figure 2).

The possible effects of vitamin E supplementation on NAFLD have been assessed in different intervention trials and the results of these trials have been examined in two meta-analyses [[149],[150]]. Briefly, vitamin E supplementation in patients with NAFLD reduces significantly liver enzymes, liver steatosis, inflammation and hepatocellular ballooning compared to control treatments. Moreover, in patients with NASH, vitamin E supplementation seems to reduce fibrosis as well. Despite the positive results of these meta-analyses, it is important to underline some limitations such as the variability in daily dosage of vitamin E, the length of treatment, and the small sample size of the studies, except for the PIVENS and the TONIC studies [[151],[152]]. Furthermore, some concerns must be underlined about the possible negative effects of high doses of vitamin E (>400 IU/day) on all-cause mortality [[153]].

2.4.4. Vitamin C

Vitamin C is a soluble vitamin and its major dietary forms l-ascorbic and dehydroascorbic acids are largely found in vegetables and fresh fruits [[154]]. Vitamin C plays a key role in many physiological functions for human health; it is essential for the activity of the enzymes implicated in the synthesis of catecholamines, carnitine and collagen; and it is a powerful antioxidant and acts as a free radical scavenger [[155]].

In the last few years, noteworthy epidemiological literature has shown an inverse correlation between vitamin C deficiency and some chronic diseases, as obesity, hypertension, and CVD [[156]]. The results of epidemiological studies are conflicting about a possible relation between vitamin C and NAFLD. In fact, Ferolla et al. [[157]] reported that patients with NAFLD were unable to achieve the optimal intake of vitamin C, and similar findings were reported by Musso et al. [[47]] and Canbakan et al. [[158]], who analyzed the intake of vitamin C in patients with NASH. Conversely, in other cross-sectional studies no relation between dietary vitamin C intake and presence of NAFDL or NASH was observed [[159],[160],[161]]. These conflicting results may be related to ethnicity and differences in disease grade (NAFL or NASH); furthermore, it should be considered that in many studies the dietary intake of vitamin C was considered with no evaluation of plasma vitamin C levels.

Theoretically, vitamin C could play a beneficial role in NAFLD by acting as powerful antioxidant and as free radical scavenger. In in vitro models, vitamin C can reduce reactive oxygen species formation and improve the activity of glutathione peroxidase and superoxide dismutase [[162]]. Furthermore, vitamin C can promote the production of adiponectin an adipose tissue protein apparently able to decrease insulin resistance and inflammation in humans [[163]] (Figure 2).

To the best of our knowledge, no clinical trial has investigated the effect of vitamin C supplementation alone on NAFLD, while some clinical trials have evaluated the effects of the combination of vitamins C and E (Table 5). The results of these trials were not concordant, two studies showing a reduction in fibrosis and NAFLD activity score evaluated on liver biopsy [[164],[165]], two studies showing no effects on liver fat [[166],[167]].

2.4.5. Vitamin D

Vitamin D is a lipid-soluble compound found in few foods, such as fatty fish, fish liver oils, and dairy products; it is also produced in the skin after ultraviolet irradiation. Vitamin D2 and vitamin D3, also called ergocalciferol and cholecalciferol, are the two main forms of vitamin D. Vitamin D plays a prominent role in calcium and phosphorus metabolism and is essential for bone health, promoting bone growth and remodeling. In the last decade, it has become evident that vitamin D also presents extra-skeletal effects, including metabolic effects, neuromuscular and immune functions [[168]].

A growing body of literature has shown that serum levels of vitamin D are inversely associated with insulin resistance, metabolic syndrome, CVD, diabetes and NAFLD [[169],[170],[171]]. A meta-analysis showed that subjects with NAFLD were 26% more likely to present vitamin D deficit than controls [[172]]. Vitamin D receptors are widely expressed in the liver and can explain the possible effect of vitamin D on NAFLD. Vitamin D may down-regulate the expression of the NF-κB involved in the transcription of inflammatory cytokines and improve the expression of PPAR-α in the liver [[173]]. Furthermore, it has been observed that vitamin D increases adiponectin secretion and decreases lipolysis in adipose tissue [[174]], improves the expression of GLUT-4 receptor in skeletal muscle [[175]] and promotes insulin secretion [[176]]. All these effects mediated by the specific vitamin D receptor could reduce liver fat content (Figure 2).

To date, very few clinical trials have investigated the effects of vitamin D supplementation on NAFLD (Table 6).

Two of them [[177],[178]] showed no effect of vitamin D supplementation on liver enzymes, liver fat content or hepatic biomarkers of injury and fibrogenesis, i.e., CK-18 and N-terminal Procollagen III Propeptide. In the third one [[179]], the effect of vitamin D supplemented to a hypocaloric diet was evaluated compared to a hypocaloric diet. Liver enzymes and liver fat content evaluated by US were significantly reduced by vitamin D independently of weight loss, which was similar in the two groups.

3. Conclusions

NAFLD is the most common chronic liver disease in the industrialized world and will become one of the most important public health challenges in the coming decades for its hepatic and extra-hepatic related complications. At present, lifestyle intervention including hypocaloric diet and regular physical exercise represents the mainstay of NAFLD management. Apart from the caloric restriction alone, changes in the quality of the diet modulating either the macro- or the micronutrient composition can also markedly affect the clinical evolution of NAFLD offering a more realistic and feasible alternative for NAFLD treatment. We tried to review the relevant data available from intervention studies in humans. Unfortunately, data are rather scant and characterized by methodological limitations, and the results are often discordant.

Notwithstanding, the following conclusions can be drawn:

Data are reasonably convincing for the possible effects of dietary macronutrients on liver fat content. In fact, SFA increase liver fat content and replacing SFA with MUFA or n-6 PUFA reduces liver fat, while the effectiveness of n-3 PUFA supplementation is still controversial.

In terms of other dietary components (polyphenols) and micronutrients, data are not yet convincing, and any effect would refer especially to liver inflammation and fibrosis more than to fat content. Only for vitamin E supplementation, data are more convincing, even if concerns may be present for high vitamin E supplementation considering possible negative effects on all cause-mortality.

Similar conclusions can also be drawn for NAFLD in children and adolescents [[180]].

Therefore, based on the available evidence in humans, precise recommendations on the quality of diet to be used for the prevention and treatment of NAFLD may not be given. More carefully conducted intervention studies are needed: it is very likely that the “optimal diet” for NAFLD should be based on different dietary modifications, i.e., a multifactorial diet, able to act both on the deposition of excess fat in the liver and on the other pathways leading from liver fat deposition to NASH and fibrosis. However, this hypothesis needs to be substantiated by appropriate intervention studies in humans.

References

  1. J.T. HaasS. FrancqueB. StaelPathophysiology and mechanisms of nonalcoholic fatty liver diseaseAnnu. Rev. Physiol.20167818120510.1146/annurev-physiol-021115-10533126667070
  2. S.M. FrancqueD. van der GraaffW.J. KwantenNon-alcoholic fatty liver disease and cardiovascular risk: Pathophysiological mechanisms and implicationsJ. Hepatol.20166542544310.1016/j.jhep.2016.04.00527091791
  3. N. ChalasaniZ. YounossiJ.E. LavineA.M. DiehlE.M. BruntK. CusiM. CharltonA.J. SanyalThe Diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the study of liver diseases, American College of Gastroenterology, and the American Gastroenterological AssociationHepatology2012552005202310.1002/hep.2576222488764
  4. B.A. Neuschwander-TetriS.H. CaldwellNonalcoholic steatohepatitis: Summary of an AASLD single topic conferenceHepatology2003371202121910.1053/jhep.2003.5019312717402
  5. Z.M. YounossiA.B. KoenigD. AbdelatifY. FazelL. HenryM. WymerGlobal epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomesHepatology201664738410.1002/hep.2843126707365
  6. K.C. YangH.F. HungC.W. LuH.H. ChangL.T. LeeK.C. HuangAssociation of non-alcoholic fatty liver disease with metabolic syndrome independently of central obesity and insulin resistanceSci. Rep.201662703410.1038/srep2703427246655
  7. L. BozzettoG. AnnuzziM. RagucciO. Di DonatoG. Della PepaG. Della CorteE. GriffoG. AnniballiA. GiaccoM. ManciniInsulin resistance, postprandial GLP-1 and adaptive immunity are the main predictors of NAFLD in a homogeneous population at high cardiovascular riskNutr. Metab. Cardiovasc. Dis.20162662362910.1016/j.numecd.2016.01.01127134062
  8. A. López-SuárezJ.M. GuerreroJ. Elvira-GonzálesM. Beltrán-RoblesF. Cañas-HormigoA. Bascuñana-QuirellNonalcoholic fatty liver disease is associated with blood pressure in hypertensive and nonhypertensive individuals from the general population with normal levels of alanine aminotransferaseEur. J. Gastroenterol. Hepatol.2011231011101710.1097/MEG.0b013e32834b8d5221915061
  9. M. BlachierH. LeleuM. Peck-RadosavljevicD.C. VallaF. Roudot-ThoravalThe burden of liver disease in Europe: A review of available epidemiological dataJ. Hepatol.20135859360810.1016/j.jhep.2012.12.00523419824
  10. H. YamazakT. TsuboyaK. TsujiM. DohkeH. MaguchiIndependent association between improvement of nonalcoholic fatty liver disease and reduced incidence of type 2 diabetes mellitusDiabetes Care2015381673167910.2337/dc15-014026156527
  11. H. BushP. GolabiZ.M. YounossiPediatric non-alcoholic fatty liver diseaseChildren201744810.3390/children406004828598410
  12. P. AnguloLong-term mortality in nonalcholic fatty liver disease: Is liver histology of any prognostic significance?Hepatology20105137337510.1002/hep.2352120101746
  13. S. BellentaniThe epidemiology of non-alcoholic fatty liver diseaseLiver Int.201737S81S8410.1111/liv.1329928052624
  14. C.D. ByrneG. TargherNAFLD: A multisystem diseaseJ. Hepatol.201562S47S6410.1016/j.jhep.2014.12.01225920090
  15. L. BozzettoA. PrinsterM. ManciniR. GiaccoC. De NataleM. SalvatoreG. RiccardiA.A. RivelleseG. AnnuzziLiver fat in obesity: Role of type 2 diabetes mellitus and adipose tissue distributionEur. J. Clin. Investig.201141394410.1111/j.1365-2362.2010.02372.x20825466
  16. M. MarcuccilliM. ChoncholNAFLD and chronic kidney diseaseInt. J. Mol. Sci.20161756210.3390/ijms1704056227089331
  17. C.P. DayO.F. JamesSteatohepatitis: A tale of two “hits”?Gastroenterology199811484284510.1016/S0016-5085(98)70599-29547102
  18. J.K. DowmanJ.W. TomlinsonP.N. NewsomePathogenesis of non-alcoholic fatty liver diseaseQ. J. Med.2010103718310.1093/qjmed/hcp15819914930
  19. K.L. DonnellyC.I. SmithS.J. SchwarzenbergJ. JessurunM.D. BoldtE.J. ParksSources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver diseaseJ. Clin. Investig.20051151343135110.1172/JCI2362115864352
  20. P. NguyenV. LerayM. DiezS. SerisierJ. Le Bloc’hB. SiliartH. DumonLiver lipid metabolismJ. Anim. Physiol. Anim. Nutr.20089227228310.1111/j.1439-0396.2007.00752.x18477307
  21. S. AlamG. MustafaM. AlamN. AhmadInsulin resistance in development and progression of nonalcoholic fatty liver diseaseWorld J. Gastrointest. Pathophysiol.2016721121710.4291/wjgp.v7.i2.21127190693
  22. M. BasaranogluFrom fatty liver to fibrosis: A tale of “second hit”World J. Gastroenterol.2013191158116510.3748/wjg.v19.i8.115823483818
  23. D.G. TiniakosM.B. VosE.M. BruntNonalcoholic fatty liver disease: Pathology and pathogenesisAnnu. Rev. Pathol.2010514517110.1146/annurev-pathol-121808-10213220078219
  24. E. BuzzettiM. PinzaniE.A. TsochatzisThe multiple–hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)Metabolism2016651038104810.1016/j.metabol.2015.12.01226823198
  25. H. KitadeG. ChenY. NiT. OtaNonalcoholic fatty liver disease and insulin resistance: New insights and potential new treatmentsNutrients2017938710.3390/nu904038728420094
  26. Z. MokhtariD.L. GibsonA. HekmatdoostNonalcoholic fatty liver disease, the gut microbiome, and dietAdv. Nutr.2017824025210.3945/an.116.01315128298269
  27. S. SookoianC.J. PirolaGenetic predisposition in nonalcoholic fatty liver diseaseClin. Mol. Hepatol.20172311210.3350/cmh.2016.010928268262
  28. P. DongiovanniL. ValentiA Nutrigenomic approach to non-alcoholic fatty liver diseaseInt. J. Mol. Sci.201718153410.3390/ijms1807153428714900
  29. A. NaskaA. TrichopoulouNutrigenomics: The Genome–Food InterfaceEnviron. Health Perspect.2007115A582A58918087577
  30. J.N. DavisK.A. LeR.W. WalkerS. VikmanD. Spruijt-MetzM.J. WeigensbergH. AllayeeM.I. GoranIncreased hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumptionAm. J. Clin. Nutr.2010921522152710.3945/ajcn.2010.3018520962157
  31. Q.M. AnsteeC.P. DayThe genetics of NAFLDNat. Rev. Gastroenterol. Hepatol.20131064565510.1038/nrgastro.2013.18224061205
  32. C. PirazziM. AdielsM.A. BurzaR.M. MancinaM. LevinM. StåhlmanM.R. TaskinenM. Orho-MelanderJ. PermanA. PujiaPatatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitroJ. Hepatol.2012571276128210.1016/j.jhep.2012.07.03022878467
  33. European Association for the Study of the Liver (EASL)European Association for the Study of Diabetes (EASD)European Association for the Study of Obesity (EASO)EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver diseaseJ. Hepatol.2016641388140227062661
  34. G. BedogniS. BellentaniL. MiglioliF. MasuttiM. PassalacquaA. CastiglioneC. TiribelliThe fatty liver index: A simple and accurate predictor of hepatic steatosis in the general populationBMC Gastroenterol.200663310.1186/1471-230X-6-3317081293
  35. A. KotronenM. PeltonenA. HakkarainenK. SevastianovaR. BergholmL.M. JohanssonN. LundbomA. RissanenM. RidderstråleL. GroopPrediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factorsGastroenterology200913786587210.1053/j.gastro.2009.06.00519524579
  36. T. PoynardG. LassaillyE. DiazK. ClementR. CaïazzoJ. TordjmanM. MunteanuH. PerazzoB. DemolR. CallafePerformance of biomarkers FibroTest, ActiTest, SteatoTest, and NashTest in patients with severe obesity: Meta-analysis of individual patient dataPLoS ONE20127e3032510.1371/journal.pone.003032522431959
  37. S. SaadehZ.M. YounossiE.M. RemerT. GramlichJ.P. OngM. HurleyK.D. MullenJ.N. CooperM.J. SheridanThe utility of radiological imaging in nonalcoholic fatty liver diseaseGastroenterology200212374575010.1053/gast.2002.3535412198701
  38. M. ManciniA. PrinsterG. AnnuzziR. LiuzziR. GiaccoC. MedagliM. CremoneG. ClementeS. MaureaG. RiccardiSonographic hepatic-renal ratio as indicator of hepatic steatosis: Comparison with (1)H magnetic resonance spectroscopyMetabolism2009581724173010.1016/j.metabol.2009.05.03219716568
  39. J. GuoS.L. FriedmanToll-like receptor 4 signaling in liver injury and hepatic fibrogenesisFibrogenes. Tissue Repair201032110.1186/1755-1536-3-2120964825
  40. European Association for the Study of the LiverAsociacion Latinoamericana para el Estudio del HigadoEASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosisJ. Hepatol.20156323726425911335
  41. V.W. WongJ. VergniolG.L. WongJ. FoucherH.L. ChanB. Le BailP.C. ChoiM. KowoA.W. ChanW. MerroucheDiagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver diseaseHepatology20105145446210.1002/hep.2331220101745
  42. K. ToshimitsuB. MatsuuraI. OhkuboT. NiiyaS. FurukawaY. HiasaM. KawamuraK. EbiharaM. OnjiDietary habits and nutrient intake in non-alcoholic steatohepatitisNutrition200723465210.1016/j.nut.2006.09.00417140767
  43. A. NaskaA. TrichopoulouBack to the future: the Mediterranean diet paradigmNutr. Metab. Cardiovasc. Dis.20142421621910.1016/j.numecd.2013.11.00724462051
  44. D.F. RomagnoloO.I. SelminMediterranean diet and prevention of chronic diseasesNutr. Today201710.1097/NT.0000000000000228
  45. S. Zelber-SagiF. SalomoneL. MlynarskyThe Mediterranean dietary pattern as the diet of choice for non-alcoholic fatty liver disease: Evidence and plausible mechanismsLiver Int.20173793694910.1111/liv.1343528371239
  46. J.P. AllardE. AghdassiS. MohammedM. RamanG. AvandB.M. ArendtP. JalaliT. KandasamyN. PrayitnoM. ShermanNutritional assessment and hepatic fatty acid composition in non-alcoholic fatty liver disease (NAFLD): A cross-sectional studyJ. Hepatol.20084830030710.1016/j.jhep.2007.09.00918086506
  47. G. MussoR. GambinoF. De MichieliM. CassaderM. RizzettoM. DurazzoE. FagàB. SilliG. PaganoDietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitisHepatology20033790991610.1053/jhep.2003.5013212668986
  48. J. WesterbackaK. LammiA.M. HäkkinenA. RissanenI. SalminenA. AroH. Yki-JärvinenDietary fat content modifies liver fat in overweight nondiabetic subjectsJ. Clin. Endocrinol. Metab.2005902804280910.1210/jc.2004-198315741262
  49. F. RosqvistD. IggmanJ. KullbergJ. CedernaesH.E. JohanssonA. LarssonL. JohanssonH. AhlströmP. ArnerI. DahlmanOverfeeding polyunsaturated and saturated fat causes distinct effects on liver and visceral fat accumulation in humansDiabetes2014632356236810.2337/db13-162224550191
  50. J. CaoD.L. DaiL. YaoH.H. YuB. NingQ. ZhangW.H. ChengW. ShenZ.X. YangSaturated fatty acid induction of endoplasmic reticulum stress and apoptosis in human liver cells via the PERK/ATF4/CHOP signaling pathwayMol. Cell. Biochem.201236411512910.1007/s11010-011-1211-922246806
  51. J. LinR. YangP.T. TarrP.H. WuC. HandschinS. LiW. YangL. PeiM. UldryP. TontonozHyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBPCell200512026127310.1016/j.cell.2004.11.04315680331
  52. A.K. LeamyR.A. EgnatchikJ.D. YoungMolecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver diseaseProg. Lipid Res.20135216517410.1016/j.plipres.2012.10.00423178552
  53. L. BozzettoA. PrinsterG. AnnuzziL. CostagliolaA. MangioneA. VitelliR. MazzarellaM. LongobardoM. ManciniC. VigoritoLiver fat is reduced by an isoenergetic MUFA diet in a controlled randomized study in type 2 diabetic patientsDiabetes Care2012351429143510.2337/dc12-003322723581
  54. M.C. RyanC. ItsiopoulosT. ThodisG. WardN. TrostS. HofferberthK. O’DeaP.V. DesmondN.A. JohnsonA.M. WilsonThe Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver diseaseJ. Hepatol.20135913814310.1016/j.jhep.2013.02.01223485520
  55. P. NigamS. BhattA. MisraD.S. ChadhaM. VaidyaJ. DasguptaQ.M. PashaEffect of a 6-month intervention with cooking oils containing a high concentration of monounsaturated fatty acids (olive and canola oils) compared with control oil in male Asian Indians with nonalcoholic fatty liver diseaseDiabetes Technol. Ther.20141625526110.1089/dia.2013.017824625239
  56. L.M. VarelaA. Ortega-GomezS. LopezR. AbiaF.J. MurianaB. BermudezThe effects of dietary fatty acids on the postprandial triglyceride-rich lipoprotein/apoB48 receptor axis in human monocyte/macrophage cellsJ. Nutr. Biochem.2013242031203910.1016/j.jnutbio.2013.07.00424231096
  57. J.P. DeLanyM.M. WindhauserC.M. ChampagneG.A. BrayDifferential oxidation of individual dietary fatty acids in humansAm. J. Clin. Nutr.20007290591111010930
  58. A. FerramoscaV. SavyV. ZaraOlive oil increases the hepatic triacylglycerol content in mice by a distinct influence on the synthesis and oxidation of fatty acidsBiosci. Biotechnol. Biochem.200872626910.1271/bbb.7036918175925
  59. L. BozzettoG. CostabileD. LuongoD. NaviglioV. CicalaC. PiantadosiL. PattiP. CiprianoG. AnnuzziA.A. RivelleseReduction in liver fat by dietary MUFA in type 2 diabetes is helped by enhanced hepatic fat oxidationDiabetologia2016592697270110.1007/s00125-016-4110-527650287
  60. O. HusseinM. GrosovskiE. LasriS. SvalbU. RavidN. AssyMonounsaturated fat decreases hepatic lipid content in non-alcoholic fatty liver disease in ratsWorld. J. Gastroenterol.20071336136810.3748/wjg.v13.i3.36117230603
  61. A.A. RivelleseR. GiaccoG. AnnuzziC. De NataleL. PattiL. Di MarinoV. MinervaG. CostabileC. SantangeloR. MasellaEffects of monounsaturated vs. saturated fat on postprandial lipemia and adipose tissue lipases in type 2 diabetesClin. Nutr.20082713314110.1016/j.clnu.2007.07.00517765364
  62. A.M. ZivkovicJ.B. GermanA.J. SanyalComparative review of diets for the metabolic syndrome: Implications for nonalcoholic fatty liver diseaseAm. J. Clin. Nutr.20078628530017684197
  63. E. Juárez-HernándezN.C. Chávez-TapiaM. UribeV.J. Barbero-BecerraRole of bioactive fatty acids in nonalcoholic fatty liver diseaseNutr. J.2016157210.1186/s12937-016-0191-827485440
  64. H. BjermoD. IggmanJ. KullbergI. DahlmanL. JohanssonL. PerssonJ. BerglundK. PulkkiS. BasuM. UusitupaEffects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: A randomized controlled trialAm. J. Clin. Nutr.2012951003101210.3945/ajcn.111.03011422492369
  65. V. NobiliA. AlisiG. MussoE. ScorelttiP.C. CalderC.D. ByrneOmega-3 fatty acids: Mechanisms of benefit and therapeutic effects in pediatric and adult NAFLDCrit. Rev. Clin. Lab. Sci.20165310612010.3109/10408363.2015.109210626463349
  66. L. SpadaroO. MaglioccoD. SpampinatoS. PiroC. OliveriC. AlagonaG. PapaA.M. RabuazzoF. PurrelloEffects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver diseaseDig. Liver Dis.20084019419910.1016/j.dld.2007.10.00318054848
  67. E. ScorlettiL. BhatiaK.G. McCormickG.F. CloughK. NashL. HodsonH.E. MoysesP.C. CalderC.D. ByrneWELCOME StudyEffects of purified eicosapentaenoic and docosahexaenoic acids in non-alcoholic fatty liver disease: Results from the WELCOME studyHepatology2014601211122110.1002/hep.2728925043514
  68. F.S. ZhuS. LiuX.M. ChenZ.G. HuangD.W. ZhangEffects of n-3 polyunsaturated fatty acids from seal oils on nonalcoholic fatty liver disease associated with hyperlipidemiaWorld. J. Gastroenterol.2008146395640010.3748/wjg.14.639519009658
  69. G.L. VegaM. ChandaliaL.S. SzczepaniakS.M. GrundyEffects of n-3 fatty acids on hepatic triglyceride content in humansJ. Investig. Med.20085678078510.2310/JIM.0b013e318177024d18525453
  70. C.K. ArgoJ.T. PatrieC. LacknerT.D. HenryE.E. de LangeA.L. WeltmanN.L. ShahA.M. Al-OsaimiP. PramoonjagoS. JayakumarEffects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trialJ. Hepatol.20156219019710.1016/j.jhep.2014.08.03625195547
  71. A.J. SanyalM. AbdelmalekA. SuzukiW. CummingsM. ChojkierNo significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trialGastroenterology201414737738410.1053/j.gastro.2014.04.04624818764
  72. J.A. CussonsG.F. WattsT.A. MoriB.G. StuckeyOmega-3 fatty acid supplementation decreases liver fat content in polycystic ovary syndrome: A randomized controlled trial employing proton magnetic resonance spectroscopyJ. Clin. Endocrinol. Metab.2009943842384810.1210/jc.2009-087019622617
  73. R.C. SchugarP.A. CrawfordLow-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver diseaseCurr. Opin. Clin. Nutr. Metab. Care20121537438010.1097/MCO.0b013e328354715722617564
  74. L.G. Da Silva-SantiM. Masetto AntunesS. Martins Caparroz-AssefF. CarboneraL. Nunes MasiR. CuriJ.V. VisentainerR. Barbosa BazotteLiver fatty acid composition and inflammation in mice fed with high-carbohydrate diet or high-fat dietNutrients2016868210.3390/nu811068227801862
  75. S. ValtuenaN. PellegriniD. ArdigoD. Del RioF. NumerosoF. ScazzinaL. MontiI. ZavaroniF. BrighentiDietary glycemic index and liver steatosisAm. J. Clin. Nutr.20068413614216825687
  76. Y.A. MoonThe SCAP/SREBP pathway: A mediator of hepatic steatosisEndocrinol. Metab.20173261010.3803/EnM.2017.32.1.628116873
  77. F. ShiraniF. ZaribafA. EsmaillzadehDietary glycemic index and glycemic load in relation to cardiovascular disease risk factors: A review of current evidenceJ. Health Syst. Res.201510641654
  78. S. BawdenM. StephensonY. FalconeM. LingayaE. CiampiK. HunterF. BlighJ. SchirraM. TaylorP. MorrisIncreased liver fat and glycogen stores after consumptionof high versus low glycaemic index food: A randomized crossover studyDiabetes Obes. Metab.201719707710.1111/dom.1278427593525
  79. E. RusulA. DragomirM. PoseaMetabolic effects of low glycaemic index dietsNutr. J.20098519178721
  80. J.A. ParnellA.R. ReimerPrebiotic fiber modulation of the gut microbiota improves risk factors for obesity and the metabolic syndromeGut Microbes20123293410.4161/gmic.1924622555633
  81. K.M. UtzschneiderJ.L. Bayer-CarterM.D. ArbuckleJ.M. TidwellT.L. RichardsS. CraftBeneficial effect of a weight-stable, low-fat/low-saturated fat/low-glycaemic index diet to reduce liver fat in older subjectsBr. J. Nutr.20131091096110410.1017/S000711451200296622849970
  82. G. MisciagnaM. Del Pilar DíazD.V. CaramiaC. BonfiglioI. FrancoM.R. NovielloM. ChiloiroD.I. AbbresciaA. MirizziM. TanziEffect of a low glycemic index mediterranean diet on non-alcoholic fatty liver disease. A randomized controlled clinical trialJ. Nutr. Health Aging20162140441210.1007/s12603-016-0809-828346567
  83. M. Ramon-KrauelS.L. SalsbergC.B. EbbelingS. VossM.R. MulkernE.A. CookeC. SaraoM.M. JonasD.S. LudwigLow-glycemic-load versus low-fat diet in the treatment of fatty liver in obese childrenChild. Obes.2013925226010.1089/chi.2013.002223705885
  84. A. FraserR. AbelD.A. LawlorD. FraserA. ElhayanyA modified Mediterranean diet is associated with the greatest reduction in alanine aminotransferase levels in obese type 2 diabetes patients: results of a quasi-randomised controlled trialDiabetologia2008511616162210.1007/s00125-008-1049-118597068
  85. D. DhingraM. MichaelH. RajputR.T. PatilDietary fibre in food: A reviewJ. Food Sci. Technol.20124925526610.1007/s13197-011-0365-523729846
  86. H. Cortez-PintoL. JesusH. BarrosC. LopesM.C. MouraM.E. CamiloHow different is the dietary pattern in non-alcoholic steatohepatitis patients?Clin. Nutr.20062581682310.1016/j.clnu.2006.01.02716677739
  87. C.H. KimJ.B. KallmanC. BaiL. PawloskiC. GewaA. ArsallaM.E. SabatellaZ.M. YounossiNutritional assessments of patients with non-alcoholic fatty liver diseaseObes. Surg.20102015416010.1007/s11695-008-9549-018560947
  88. H. ZolfaghariG. AskariF. SiassiA. FeiziG. SotoudehIntake of nutrients, fiber, and sugar in patients with nonalcoholic fatty liver disease in comparison to healthy individualsInt. J. Prev. Med.201679827625763
  89. C.A. DaubioulY. HorsmansP. LambertE. DanseN.M. DelzenneEffects of oligofructose on glucose and lipid metabolism in patients with nonalcoholic steatohepatitis: Results of a pilot studyEur. J. Clin. Nutr.20055972372610.1038/sj.ejcn.160212715770222
  90. J.M. RippeT.J. AngelopoulosFructose-containing sugars and cardiovascular diseaseAdv. Nutr.2015643043910.3945/an.114.00817726178027
  91. P.M. NunesA.J. WrightA. VeltienJ.J. van AstenC.J. TackJ.G. JonesA. HeerschapDietary lipids do not contribute to the higher hepatic triglyceride levels of fructose-compared to glucose-fed miceFASEB J.2014281988199710.1096/fj.13-24120824500922
  92. W. NseirF. NassarN. AssySoft drinks consumption and nonalcoholic fatty liver diseaseWorld J. Gastroenterol.2010162579258810.3748/wjg.v16.i21.257920518077
  93. M.F. AbdelmalekA. SuzukiC. GuyA. Unalp-AridaR. ColvinR.J. JohnsonA.M. DiehlIncreased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver diseaseHepatology201051961197110.1002/hep.2353520301112
  94. J. MaC.S. FoxP.F. JacquesE.K. SpeliotesU. HoffmannC.E. SmithE. SaltzmanN.M. McKeownSugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohortsJ. Hepatol.20156346246910.1016/j.jhep.2015.03.03226055949
  95. M.J. DekkerQ. SuC. BakerA.C. RutledgeK. AdeliFructose: A highly lipogenic nutrient implicated in insulin resistance, hepatic steatosis, and the metabolic syndromeAm. J. Physiol. Endocrinol. Metab.2010299E685E69410.1152/ajpendo.00283.201020823452
  96. A. RebolloN. RoglansM. AlegretJ.C. LagunaWay back for fructose and liver metabolism: Bench side to molecular insightsWorld J. Gastroenterol.2012186552655910.3748/wjg.v18.i45.655223236229
  97. M. BasaranogluG. BasaranogluE. BugianesiCarbohydrate intake and nonalcoholic fatty liver disease: Fructose as a weapon of mass destructionHepatobiliary Surg. Nutr.2015410911626005677
  98. N. BernardesP. AyyappanK. De AngelisA. BagchiG. AkolkarD. da Silva DiasA. Belló-KleinExcessive consumption of fructose causes cardiometabolic dysfunctions through oxidative stress and inflammationCan. J. Physiol. Pharmacol.20171011310.1139/cjpp-2016-066328187269
  99. J. MohamedA.H. Nazratun NafizahA.H. ZariyanteyS.B. BudinMechanisms of diabetes-induced liver damage the role of oxidative stress and inflammationSult. Qaboos Univ. Med. J.201616e132e14110.18295/squmj.2016.16.02.00227226903
  100. E.T. Ngo SockK.A. LeM. IthR. KreisC. BoeschL. TappyEffects of a short-term overfeeding with fructose or glucose in healthy young malesBr. J. Nutr.201010393994310.1017/S000711450999281919930762
  101. G. SilbernagelJ. MachannS. UnmuthF. SchickN. StefanH.U. HaringA. FritscheEffects of 4-week very-high-fructose/glucose diets on insulin sensitivity, visceral fat and intrahepatic lipids: An exploratory trialBr. J. Nutr.2011106798610.1017/S000711451000574X21396140
  102. M. MaerskA. BelzaH. Stodkilde-JorgensenS. RinggaardE. ChabanovaH. ThomsenS.B. PedersenA. AstrupB. RichelsenSucrose-sweetened beverages increase fat storage in the liver, muscle, and visceralfat depot: A6-mo randomized intervention studyAm. J. Clin. Nutr.20129528328910.3945/ajcn.111.02253322205311
  103. S. BravoJ. LowndesS. SinnettZ. YuJ. RippeConsumption of sucrose and high-fructose corn syrup does not increase liver fat or ectopic fat deposition in musclesAppl. Physiol. Nutr. Metab.20133868168810.1139/apnm-2012-032223724887
  104. V. LecoultreL. EgliG. CarrelF. TheytazR. KreisP. SchneiterA. BossK. ZwygartK.-A. LeM. BortolottiEffects of fructose and glucose overfeeding on hepatic insulin sensitivity and intrahepatic lipids in healthy humansObesity20132178278510.1002/oby.2037723512506
  105. I. AeberliP.A. GerberM. HochuliS. KohlerS.R. HaileI. Gouni-BertholdG.A. SpinasK. BerneisLow to moderate sugar-sweetened beverage consumption impairs glucose and lipid metabolism and promotes inflammation in healthy young men: A randomized controlled trialAm. J. Clin. Nutr.20119447948510.3945/ajcn.111.01354021677052
  106. K.A. LêD. FaehR. StettlerM. IthR. KreisP. VermathenC. BoeschE. RavussinL. TappyA 4-wk high-fructose diet alters lipid metabolism without affecting insulin sensitivity or ectopic lipids in healthy humansAm. J. Clin. Nutr.2006841374137917158419
  107. M.R. TaskinenS. SöderlundL.H. BoglA. HakkarainenN. MatikainenK.H. PietiläinenS. RäsänenN. LundbomE. BjörnsonB. EliassonAdverse effects of fructose on cardiometabolic risk factors and hepatic lipid metabolism in subjects with abdominal obesityJ. Intern. Med.201728218720110.1111/joim.1263228548281
  108. S. ChiuJ.L. SievenpiperR.J. de SouzaA.I. CozmaA. MirrahimiA.J. CarletonV. HaM. Di BuonoA.L. JenkinsL.A. LeiterEffect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis of controlled feeding trialsEur. J. Clin. Nutr.20146841642310.1038/ejcn.2014.824569542
  109. J. MaM.C. KarlsenM. ChungP.F. JacquesE. SaltzmanC.E. SmithC.S. FoxN.M. McKeownPotential link between excess added sugar intake and ectopic fat: A systematic review of randomized controlled trialsNutr. Rev.201574183210.1093/nutrit/nuv04726518034
  110. R.D. JohnstonM.C. StephensonH. CrosslandS.M. CordonE. PalcidiE.F. CoxM.A. TaylorG.P. AithalI.A. MacdonaldNo difference between high-fructose and high-glucose diets on liver triacylglycerol or biochemistry in healthy overweight menGastroenterology20131451016102510.1053/j.gastro.2013.07.01223872500
  111. L. PichonJ.F. HuneauG. FromentinD. TomeA high-protein, high-fat, carbohydrate-free diet reduces energy intake, hepatic lipogenesis, and adiposity in ratsJ. Nutr.20061361256126016614413
  112. L. AlferinkJ.C.B. Kiefte-deJongJ.D. SchoufourP. TaimrA.M. IkramH.L.A. JanssenH.J. MetselaarO.H. FrancoS.D. MuradAnimal protein is the most important macronutrient associated with non-alcoholic fatty liver disease in overweight participants: The Rotterdam StudyJ. Hepatol.201766S5010.1016/S0168-8278(17)30363-X
  113. S. Zelber-SagiD. Nitzan-KaluskiZ. HalpernR. OrenLong term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): A population based studyJ. Hepatol.20074771171710.1016/j.jhep.2007.06.02017850914
  114. M. BortolottiE. MaioloM. CorazzaE. Van DijkeP. SchneiterA. BossG. CarrelV. GiustiK.A. LêD.G.Q. ChongEffects of a whey protein supplementation on intrahepatocellular lipids in obese female patientsClin. Nutr.20113049449810.1016/j.clnu.2011.01.00621288612
  115. S.M.B. DuarteJ. FaintuchJ.T. StefanoM.B.S.D. OliveiraD.F.D.C. MazoF. RabeloD. VanniM.A. NogueiraF.J. CarhilloC.P.M.S.D. OliveiraHypocaloric high-protein diet improves clinical and biochemical markers in patients with nonalcoholic fatty liver disease (NAFLD)Nutr. Hosp.2014299410124483967
  116. A.H. KaniS.M. AlavianA. EsmaillzadehP. AdibiL. AzadbakhtEffects of a novel therapeutic diet on liver enzymes and coagulating factors in patients with non-alcoholic fatty liver disease: A parallel randomized trialNutrition20143081482110.1016/j.nut.2013.11.00824984998
  117. G.P.P. LimaF. VianelloC.R. CorrêaR.A. da Silva CamposM.G. BorguiniPolyphenols in fruits and vegetables and its effect on human healthFood Nutr. Sci.201451065108210.4236/fns.2014.511117
  118. J. Pérez-JiménezL. FezeuM. TouvierN. ArnaultC. ManachS. HercbergP. GalanA. ScalbertDietary intake of 337 polyphenols in French adultsAm. J. Clin. Nutr.2011931220122810.3945/ajcn.110.00709621490142
  119. D. Del RioA. Rodriguez-MateosJ.P. SpencerM. TognoliniG. BorgesA. CrozierDietary (poly)phenolics in human health: Structures, bioavailability, and evidence of protective effects against chronic diseasesAntioxid. Redox Signal.2013181818189210.1089/ars.2012.458122794138
  120. G. AnnuzziL. BozzettoG. CostabileR. GiaccoA. MangioneG. AnniballiM. VitaleC. VetraniP. CiprianoG. Della CorteDiets naturally rich in polyphenols improve fasting and postprandial dyslipidemia and reduce oxidative stress: a randomized controlled trialAm. J. Clin. Nutr.20149946347110.3945/ajcn.113.07344524368433
  121. F. SalomoneJ. GodosS. Zelber-SagiNatural anti-oxidants for nonalcoholic fatty liver disease: Molecular targets and clinical perspectivesLiver Int.20163652010.1111/liv.1297526436447
  122. J.F. LiuY. MaY. WangZ. DuJ.K. ShenH.L. PengReduction of lipid accumulation in HepG2 cells by luteolin is associated with activation of AMPK and mitigation of oxidative stressPhytother. Res.20112558859610.1002/ptr.330520925133
  123. S. ChenX. ZhaoL. RanJ. WanX. WangJ. QinF. ShuY. GaoL. YuanQ. ZhangResveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: A randomized controlled trialDig. Liver Dis.20154722623210.1016/j.dld.2014.11.01525577300
  124. I. Rodriguez-RamiroD. VauzourA.M. MinihanePolyphenols and non-alcoholic fatty liver disease: Impact and mechanismsProc. Nutr. Soc.201675476010.1017/S002966511500421826592314
  125. L. BozzettoG. AnnuzziG. PaciniG. CostabileC. VetraniM. VitaleE. GriffoA. GiaccoC. De NataleS. CocozzaPolyphenol-rich diets improve glucose metabolism in people at high cardiometabolic risk: A controlled randomised intervention trialDiabetologia2015581551156010.1007/s00125-015-3592-x25906754
  126. J. ShangL.L. ChenF.X. XiaoH. SunH.C. DingH. XiaoResveratrol improves non-alcoholic fatty liver disease by activating AMP-activated protein kinaseActa Pharmacol. Sin.20082969870610.1111/j.1745-7254.2008.00807.x18501116
  127. H.C. ChangC.H. PengD.M. YehE.S. KaoC.J. WangHibiscus sabdariffa extract inhibits obesity and fat accumulation, and improves liver steatosis in humansFood Funct.2014573473910.1039/c3fo60495k24549255
  128. H. GuoR. ZhongY. LiuX. JiangX. TangZ. LiM. XiaW. LingEffects of bayberry juice on inflammatory and apoptotic markers in young adults with features of non-alcoholic fatty liver diseaseNutrition20143019820310.1016/j.nut.2013.07.02324377455
  129. I. SudaF. IshikawaM. HatakeyamaM. MiyawakiT. KudoK. HiranoA. ItoO. YamakawaS. HoriuchiIntake of purple sweet potato beverage affects on serum hepatic biomarker levels of healthy adult men with borderline hepatitisEur. J. Clin. Nutr.200862606710.1038/sj.ejcn.160267417299464
  130. R. SakataT. NakamuraT. TorimuraT. UenoS. SataGreen tea with high-density catechins improves liver function and fat infiltration in non alcoholic fatty liver disease (NAFLD) patients: A double-blind placebo-controlled studyInt. J. Mol. Med.20133298999410.3892/ijmm.2013.150324065295
  131. M.M. PoulsenP.F. VestergaardB.F. ClasenY. RadkoL.P. ChristensenH. Stødkilde-JørgensenN. MøllerN. JessenS.B. PedersenJ.O.L. JørgensenHigh-dose resveratrol supplementation in obese men: An investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body compositionDiabetes2013621186119510.2337/db12-097523193181
  132. S. HeebøllM. KreuzfeldtS. Hamilton-DutoitM.P. PoulsenH. Stødkilde-JørgensenH.J. MøllerN. JessenK. ThorsenY.K. HellbergS.B. PedersenPlacebo-controlled, randomised clinical trial: high dose resveratrol treatment for non-alcoholic fatty liver diseaseScand. J. Gastroenterol.20165145646310.3109/00365521.2015.110762026784973
  133. V.S. ChachayG.A. MacdonaldJ.H. MartinJ.P. WhiteheadT.M. O’Moore–SullivanP. LeeM. FranklinK. KleinP.J. TaylorM. FergusonResveratrol Does Not Benefit Patients With Nonalcoholic Fatty Liver DiseaseClin. Gastroenterol. Hepatol.2014122092210310.1016/j.cgh.2014.02.02424582567
  134. F. FaghihzadehP. AdibiR. RafieiA. HekmatdoostResveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver diseaseNutr. Res.20143483784310.1016/j.nutres.2014.09.00525311610
  135. M.K. KwokG.M. LeungC.M. SchoolingHabitual coffee consumption and risk of type 2 diabetes, ischemic heart disease, depression and Alzheimer’s disease: A Mendelian randomization studySci. Rep.201663650010.1038/srep3650027845333
  136. K. WijarnpreechaC. ThongprayoonP. UngprasertCoffee consumption and risk of nonalcoholic fatty liver disease: A systematic review and meta-analysisEur. J. Gastroenterol. Hepatol.201729e8e1210.1097/MEG.000000000000077627824642
  137. S. MarventanoF. SalomoneJ. GodosF. PluchinottaD. Del RioA. MistrettaG. GrossoCoffee and tea consumption in relation with non-alcoholic fatty liver and metabolic syndrome: A systematic review and meta-analysis of observational studiesClin. Nutr.2016351269128110.1016/j.clnu.2016.03.01227060021
  138. H. ShenA.C. RodriguezA. ShianiS. LipkaG. ShahzadA. KumarP. MustacchiaAssociation between caffeine consumption and nonalcoholic fatty liver disease: A systemic review and meta-analysisTher. Adv. Gastroenterol.2016911312010.1177/1756283X1559370026770272
  139. S. ChenN.C. TeohS. ChitturiG.C. FarrellCoffee and non-alcoholic fatty liver disease: Brewing evidence for hepatoprotection?J. Gastroenterol. Hepatol.20142943544110.1111/jgh.1242224199670
  140. P. VitaglioneF. MoriscoG. MazzoneD.C. AmorusoM.T. RibeccoA. RomanoV. FoglianoN. CaporasoG. D’ArgenioCoffee reduces liver damage in a rat model of steatohepatitis: The underlying mechanisms and the role of polyphenols and melanoidinsHepatology2010521652166110.1002/hep.2390221038411
  141. E. NikiM.G. TraberA history of vitamin EAnn. Nutr. Metab.20126120721210.1159/00034310623183290
  142. M.G. TraberVitamin E regulatory mechanismsAnnu. Rev. Nutr.20072734736210.1146/annurev.nutr.27.061406.09381917439363
  143. S. RizviS.T. RazaF. AhmedA. AhmadS. AbbasF. MahdiThe Role of Vitamin E in Human Health and Some DiseasesSult. Qaboos Univ. Med. J.201414e158e165
  144. Y.M. NanW.J. WuN. FuB.L. LiangR.Q. WangL.X. LiS.X. ZhaoJ.M. ZhaoJ. YuAntioxidants vitamin E and 1-aminobenzotriazole prevent experimental non-alcoholic steatohepatitis in miceScand. J. Gastroenterol.2009441121113110.1080/0036552090311491219606393
  145. N. PhungN. PeraG. FarrellI. LeclercqJ.Y. HouJ. GeorgePro-oxidant-mediated hepatic fibrosis and effects of antioxidant intervention in murine dietary steatohepatitisInt. J. Mol. Med.20092417118019578790
  146. J.S. SodenM.W. DevereauxJ.E. HaasE. GumprichtR. DahlJ. GrallaM.G. TraberR.J. SokolSubcu­taneous vitamin E ameliorates liver injury in an in vivo model of steatocholestasisHepatology20074648549510.1002/hep.2169017659596
  147. T. HasegawaM. YonedaK. NakamuraI. MakinoA. TeranoPlasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: A pilot studyAliment. Pharmacol. Ther.2001151667167210.1046/j.1365-2036.2001.01083.x11564008
  148. D.B. WilliamsZ. WanB.C. FrierR.C. BellC.J. FieldD.C. WrightDietary supplementation with vitamin E and C attenuates dexamethasone-induced glucose intolerance in ratsAm. J. Physiol. Regul. Integr. Comp. Physiol.2012302495810.1152/ajpregu.00304.201122031784
  149. K. SatoM. GoshoT. YamamotoY. KobayashiN. IshiiT. OhashiY. NakadeK. ItoY. FukuzawaM. YonedaVitamin E has a beneficial efficacy on nonalcoholic fatty liver disease: A meta-analysis of randomized controlled trialsNutriton201531923930
  150. H.F. JiY. SunL. ShenEffect of vitamin E supplementation on aminotransferase levels in patients with NAFLD, NASH and CHC: Results from a meta-analysisNutrition20143098699110.1016/j.nut.2014.01.01624976430
  151. A.J. SanyalN. ChalasaniK.V. KowdleyA. McCulloughA.M. DiehlN.M. BassB.A. Neuschwander-TetriJ.E. LavineJ. TonasciaA. UnalpPioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitisN. Engl. J. Med.20103621675168510.1056/NEJMoa090792920427778
  152. J.E. LavineJ.B. SchwimmerM.L. Van NattaJ.P. MollestonK.F. MurrayP. RosenthalS.H. AbramsA.O. ScheimannA.J. SanyalN. ChalasaniNonalcoholic steatohepatitis clinical research network. effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: The TONIC randomized controlled trialJAMA20113051659166810.1001/jama.2011.52021521847
  153. E.R. MillerR. Pastor-BarriusoD. DalalR.A. RiemersmaL.J. AppelE. GuallarMeta-analysis: High-dosage vitamin E supplementation may increase all-cause mortalityAnn. Intern. Med.200542374610.7326/0003-4819-142-1-200501040-00110
  154. T.L. DuarteJ. LunecReview: When is an antioxidant not an antioxidant? A review of novel actions and reactions of vitamin CFree Radic. Res.20053967168610.1080/1071576050010402516036346
  155. K.A. NaiduVitamin C in human health and disease is still a mystery?Nutr. J.20032710.1186/1475-2891-2-714498993
  156. J. LykkesfeldtH.E. PoulsenIs vitamin C supplementation beneficial? Lessons learned from randomized controlled trialsBr. J. Nutr.20101031251125910.1017/S000711450999322920003627
  157. S.M. FerollaT.C. FerrariM.L. LimaT.O. ReisW.C. Tavares Jr.O.F. CoutoP.V. VidigalM.A. FaustoC.A. CoutoDietary patterns in brazilian patients with nonalcoholic fatty liver disease: A cross-sectional studyClinics201368111710.6061/clinics/2013(01)OA0323420151
  158. B. CanbakanH. SenturkV. TahanI. HatemiH. BalciT. ToptasA. SonsuzM. VeletS. AydinA. DiricanClinical, biochemical and histological correlations in a group of non-drinker subjects with non-alcoholic fatty liver diseaseActa Gastronterol. Belg.200770277284
  159. H.E. Da SilvaB.M. ArendtS.A. NoureldinG. TherapondosM. GuindiJ.P. AllardA cross-sectional study assessing dietary intake and physical activity in Canadian patients with nonalcoholic fatty liver disease vs. healthy controlsJ. Acad. Nutr. Diet.20141141181119410.1016/j.jand.2014.01.00924631112
  160. K. MadanP. BhardwajS. TharejaS.D. GuptaA. SarayaOxidant stress and antioxidant status among patients with nonalcoholic fatty liver disease (NAFLD)J. Clin. Gastroenterol.20064093093510.1097/01.mcg.0000212608.59090.0817063114
  161. D.R. MagerC. PattersonS. SoC.D. RogensteinL.J. WykesE.A. RobertsDietary and physical activity patterns in children with fatty liverEur. J. Clin. Nutr.20106462863510.1038/ejcn.2010.3520216561
  162. M.P. ValdecantosP. Perez-MatuteP. QuinteroJ.A. MartinezVitamin C, resveratrol and lipoic acid actions on isolated rat liver mitochondria: All antioxidants but differentRedox Rep.20101520721610.1179/135100010X1282644692146421062536
  163. F.J. RoseJ. WebsterJ.B. BarryL.K. PhillipsA.A. RichardsJ.P. WhiteheadSynergistic effects of ascorbic acid and thiazolidinedione on secretion of high molecular weight adiponectin from human adipocytesDiabetes Obes. Metab.2010121084108910.1111/j.1463-1326.2010.01297.x20977580
  164. S.A. HarrisonS. TorgersonP. HayashiJ. WardS. SchenkerVitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitisAm. J. Gastroenterol.2003982485249010.1111/j.1572-0241.2003.08699.x14638353
  165. V. NobiliM. MancoR. DevitoV. di CiommoD. ComparcolaM.R. SartorelliF. PiemonteM. MarcelliniP. AnguloLifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: A randomized, controlled trialHepatology20084811912810.1002/hep.2233618537181
  166. G. ErsözF. GunsarZ. KarasuS. AkayY. BaturU.S. AkarcaManagement of fatty liver disease with vitamin E and C compared to ursodeoxycholic acid treatmentTurk. J. Gastroenterol.20051612412816245220
  167. V. NobiliM. MancoR. DevitoP. CiampaliniF. PiemonteM. MarcelliniEffect of vitamin E on aminotransferase levels and insulin resistance in children with non-alcoholic fatty liver diseaseAliment. Pharmacol. Ther.2006241553156110.1111/j.1365-2036.2006.03161.x17206944
  168. L. CianferottiF. BertoldoH.A. Bischoff-FerrariO. BruyereC. CooperM. CutoloJ.A. KanisJ.M. KaufmanJ.Y. ReginsterR. RizzoliVitamin D supplementation in the prevention and management of major chronic diseases not related to mineral homeostasis in adults: Research for evidence and a scientific statement from the European society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO)Endrocrine201756245261
  169. A.G. PittasM. ChungT. TrikalinosJ. MitriM. BrendelK. PatelA.H. LichtensteinJ. LauE.M. BalkSystematic review: Vitamin D and cardiometabolic outcomesAnn. Intern. Med.201015230731410.7326/0003-4819-152-5-201003020-0000920194237
  170. I. BarchettaF. AngelicoM.D. BenM.G. BaroniP. PozzilliS. MoriniM.G. CavalloStrong association between non-alcoholic fatty liver disease (NAFLD) and low 25 (OH) vitamin D levels in an adult population with normal serum liver enzymesBMC Med.201198510.1186/1741-7015-9-8521749681
  171. G. AnnuzziG. Della PepaC. VetraniVitamin D and cardiovascular disease: Is there evidence to support the bandwagon?Curr. Atheroscler. Rep.20121452553410.1007/s11883-012-0281-922961073
  172. M. EliadesE. SpyrouN. AgrawalM. LazoF.L. BrancatiJ.J. PotterA.A. KoteishJ.M. ClarkE. GuallarR. HernaezMeta-analysis: Vitamin D and non-alcoholic fatty liver diseaseAliment. Pharmacol. Ther.20133824625410.1111/apt.1237723786213
  173. C. NingL. LiuG. LvY. YangY. ZhangR. YuY. WangJ. ZhuLipid metabolism and inflammation modulated by Vitamin D in liver of diabetic ratsLipids Health Dis.2015143110.1186/s12944-015-0030-525899686
  174. H. ShiA.W. NormanW.H. OkamuraA. SenM.B. Zemel1alpha,25-Dihydroxyvitamin D3 modulates human adipocyte metabolism via nongenomic actionFASEB J.20111527512753
  175. Q.G. ZhouF.F. HouZ.J. GuoM. LiangG.B. WangX. Zhang1,25-Dihydroxyvitamin D improved the free fatty-acid-induced insulin resistance in cultured C2C12 cellsDiabetes Metab. Res. Rev.20042445946410.1002/dmrr.87318551686
  176. J. NagpalJ.N. PandeA. BhartiaA double-blind randomized placebo controlled trial of the short-term effect of vitamin D3 supplementation on insulin sensitivity in apparently healthy, middle-aged, centrally obese menDiabet. Med.200926192710.1111/j.1464-5491.2008.02636.x19125756
  177. N. SharifiR. AmaniE. HajianiB. CheraghianDoes vitamin D improve liver enzymes, oxidative stress, and inflammatory biomarkers in adults with non-alcoholic fatty liver disease? A randomized clinical trialEndocrine201447708010.1007/s12020-014-0336-524968737
  178. I. BarchettaM. Del BenF. AngelicoM. Di MartinoA. FraioliG. La TorreR. SaulleL. PerriS. MoriniC. TibertiNo effects of oral vitamin D supplementation on non-alcoholic fatty liver disease in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trialBMC Med.2016149210.1186/s12916-016-0638-y27353492
  179. H. Lorvand AmiriS. AgahS.N. MousaviA.F. HosseiniF. ShidfarRegression of non-alcoholic fatty liver by vitamin D supplement: A double-blind randomized controlled clinical trialArch. Iran. Med.20161963163827631178
  180. P.S. GibsonS. LangA. DhawanE. FitzpatrickM.L. BlumfieldH. TrubyK.H. HartJ.B. MooreSystematic review: Nutrition and physical activity in the management of paediatric nonalcoholic fatty liver diseaseJ. Pediatr. Gastroenterol. Nutr.20176514114910.1097/MPG.000000000000162428737568
The underlying source XML for this text is taken from https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5691682/fullTextXML. The license for the article is Creative Commons Attribution. The main subject has been identified as obesity.