Insulin Resistance and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic Steatohepatitis (NASH) [1 ed.] 9781617284809, 9781616689278

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Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Nakajima, Atsushi. Insulin Resistance and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic Steatohepatitis

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Nakajima, Atsushi. Insulin Resistance and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

METABOLIC DISEASES - LABORATORY AND CLINICAL RESEARCH

INSULIN RESISTANCE AND NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)/NONALCOHOLIC STEATOHEPATITIS (NASH)

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Nakajima, Atsushi. Insulin Resistance and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic

METABOLIC DISEASES - LABORATORY AND CLINICAL RESEARCH

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INSULIN RESISTANCE AND NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)/NONALCOHOLIC STEATOHEPATITIS (NASH) MASATO YONEDA YUICHI NOZAKI KOJI FUJITA AND

ATSUSHI NAKAJIMA

Nova Biomedical Books New York Nakajima, Atsushi. Insulin Resistance and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic

Copyright © 2010 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com

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NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS.

Library of Congress Cataloging-in-Publication Data Insulin resistance and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) /I. Masato Yoneda ... [et al.]. viii, 54 p. : col. ill. ; 22 cm. Includes bibliographical references and index.

ISBN:  (eBook)

1. Fatty liver. Insulin resistance. 2. Fatty Liver --etiology. 3. Fatty Liver --physiopathology. 4. Insulin Resistance --physiology. I. Yoneda, Masato, et al. RC848.F3 I57 2010 616.3/62 2010025523

Published by Nova Science Publishers, Inc. † New York Nakajima, Atsushi. Insulin Resistance and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic

Contents vii 

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Preface Chapter I

Introduction

1 

Chapter II

NAFLD and Insulin Resistance (IR)

5 

Chapter III

Pathophysiology of NASH: Insulin Resistance, Free Fatty Acids and Cytokines

7 

Chapter IV

Adiponectin and NASH

9 

Chapter V

TNF-α and NAFLD/NASH

11 

Chapter VI

Leptin and NAFLD/NASH

13 

Chapter VII

Peroxisome Proliferators-Activated Receptors (PPARs) and NAFLD/NASH

15 

Chapter VIII

Iron Overload and NAFLD/NASH

17 

Chapter IX

Mitochondrial Abnormalities and NAFLD/NASH

19 

Chapter X

Genetic Influences in NAFLD/NASH

21 

Chapter XI

Therapeutic Strategy for NASH Patients

25 

Chapter XII

Natural History of NAFLD

29 

Chapter XIII

Conclusions

31

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vi

Contents 33 

Index

51

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References

Nakajima, Atsushi. Insulin Resistance and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic

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Preface The liver is the first organ to receive nutrients that enter the body via the intestines after a meal, and this organ plays a pivotal role in energy metabolism. Nonalcoholic fatty liver disease (NAFLD) is among the most common causes of chronic liver disease in the world and is now considered to be a component of metabolic syndrome. A wide spectrum of histological changes has been observed in NAFLD, ranging from simple steatosis, which is generally non-progressive, to nonalcoholic steatohepatitis (NASH), liver cirrhosis, liver failure, and sometimes even hepatocellular carcinoma. Histologically, the condition is characterized by macrovesicular hepatic steatosis, and diagnoses are only made in patients who do not have a history of alcohol consumption in amounts sufficient to be considered harmful to the liver. Insulin resistance is nearly universal in patients with NAFLD and nonalcoholic steatohepatitis (NASH). Although the pivotal cause of the development of NAFLD/NASH is still unknown, insulin resistance is strongly suspected of playing an important role in the development of these lesions. Type 2 diabetes, glucose intolerance and insulin resistance occur at a high frequency in patients with NAFLD, and these conditions have been shown to be of prognostic significance. Regarding the molecular mechanisms underlying insulin resistance in patients with NAFLD/NASH, cytokine-adipokine interactions are believed to be intricately involved. Insulin resistance is thought to be regulated by proinflammatory cytokines, adipokines (TNF-α, adiponectin, leptin), and peroxisome proliferator-activator receptors (PPARs). Recent reports have described the involvement of genetic factors as well as environmental

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factors in the development of insulin resistance. Genetic factors are also thought to be important in the development of NAFLD/NASH, and genetic polymorphisms of genes encoding TNF-α, adiponectin, and PPARs are reportedly associated with the development of NAFLD/NASH. Most therapeutic modalities that are already in use or under development target major pathways that are believed to be essential to the pathogenesis of NAFLD/NASH, and these therapies are often directed at improving insulin resistance via pharmacologic (thiazolidinediones, metformin), surgical, or dietary approaches. Here, the authors review recent evidence concerning insulin resistance and NAFLD/NASH as a step towards a comprehensive understanding of the pathophysiology and treatment of NAFLD/NASH.

Nakajima, Atsushi. Insulin Resistance and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic

Chapter I

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Introduction The liver is one of the most important organs associated with digestion, detoxification, production, and storage. In the liver, insulin is involved in a number of actions responsible for glucose control and lipid metabolism. In cases with insulin resistance, insulin levels are raised to overcome this resistance. The resulting effects depend on the metabolic pathway: a deficient insulin response affects glucose metabolism by increasing glucose production in the fasting state, while an elevated insulin level leads to the activation of the lipid biosynthetic pathway, resulting in the increased production of very low density lipoprotein (VLDL) and dyslipidemia. Given the central role played by the liver in lipid metabolism, any imbalance between the entry and export of lipid derivatives results in steatosis. Liver steatosis is indicated by the presence of triglycerides (TG) as lipid droplets within hepatocytes. Nonalcoholic fatty liver disease (NAFLD) is now recognized as one of the most common liver diseases in the world. NAFLD is a general term that has been adopted to cover a full spectrum of metabolic fatty liver disorders [1] and was previously recognized as a relatively benign disease observed mostly in some obese patients. In 1980, Ludwig et al. described nonalcoholic steatohepatitis (NASH), the most serious form of NAFLD, as a novel liver disease [2]. NASH is histologically characterized by zone 3-dominant hepatic steatosis with hepatocellular ballooning, lobular inflammation, and zone 3 perisinusoidal fibrosis and sometimes progresses to cirrhosis and liver failure [2, 3]. NASH is thought to be induced in two consecutive steps, the so-called two-hit

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hypothesis: excess fat accumulates in the liver, leading to necroinflammation [4] (see figure 1). This notion suggests that NAFLD is not a benign disease, but a condition with the potential to develop into liver cirrhosis. NAFLD has a worldwide distribution, and populationbased screening studies have shown that its prevalence ranges from 17% to 33% of the general population. By contrast, the prevalence of NASH, the more serious form of NAFLD, is approximately 3% in general populations and is more prevalent among obese persons [5]. In recent years, the number of obese patients has steadily increased; consequently, obesity became a major cause of morbidity and mortality in the US in the 1990s [6, 7]. Also, obesity has become one of the most important risk factors for NAFLD. For this reason, the report of Ludwig et al. had a great impact on the management of patients with NAFLD in the late 1990s.

Figure 1. Natural history of nonalcoholic steatohepatitis (NASH), from steatosis to cirrhosis. Nakajima, Atsushi. Insulin Resistance and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic

Introduction

3

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Insulin resistance is a common feature present in a number of physiological and pathological conditions in humans. NAFLD is now regarded as a component of metabolic syndrome, and type 2 diabetes may progress to NASH over a long-term period, along with additional complications such as fibrosis and cirrhosis. Steatosis and insulin resistance have a number of reciprocal relationships and can enhance each other. Herein, we review recent evidence concerning insulin resistance and NAFLD/NASH as a step towards a comprehensive understanding of the pathophysiology and treatment of NAFLD/NASH.

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Chapter II

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NAFLD and Insulin Resistance (IR) Type 2 diabetes and glucose intolerance are very frequent in patients with NAFLD, and these conditions have prognostic significance [8]. Several studies have revealed an association between the levels of liver fat and insulin resistance in patients with obesity, metabolic syndrome, or type 2 diabetes [9, 10]. Liver fat was fourfold higher in those with metabolic syndrome than in those without metabolic syndrome, and this association was independent of age, gender, and BMI [9]. The amount of liver fat has been related to the amount of subcutaneous fat and visceral fat [11], and liver fat is the most accurate indicator of insulin resistance [9]. In patients without diabetes, insulin resistance can often be assessed by calculating the homeostasis model assessment of insulin resistance (HOMA-R) or the quantitative insulin-sensitivity check index (QUICK) [12, 13]. Furthermore metabolic syndrome in patients with NAFLD is reportedly associated with greater histologic severity [14].

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Chapter III

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Pathophysiology of NASH: Insulin Resistance, Free Fatty Acids and Cytokines Insulin resistance and increased free fatty acids in the liver are probably strongly associated with NASH [15, 16]. Insulin resistance leads to fat accumulation in hepatocytes via lipolysis and hyperinsulinemia. Recently, the interplay of cytokines and adipokines in relation to NAFLD has been drawing an increasing amount of attention and research to elucidate the underlying mechanism. Insulin resistance is thought to be regulated by proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), and some adipokines, e.g., adiponectin and leptin [17, 18]. Visceral adipose tissue plays an important role in the pathogenesis of hepatic steatosis as a supplier of fat to the liver via the portal vein [19 – 21]. Adipose tissue has recently been shown to produce and secrete several bioactive substances, known as adipocytokines, including adiponectin, leptin, plasminogen activator inhibitor-1 (PAI-1), and TNFα [22 – 26]. Hyperinsulinemia induces the expression of sterol regulatory element-binding protein-1c (SREBP-1c) and hyperglycemia activates the carbohydrate response element binding protein (ChREBP), both of which increase hepatic fatty acid synthesis [27].

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Chapter IV

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Adiponectin and NASH Adiponectin is a recently discovered adipocyte-derived cytokine. It is the most abundant gene product in adipose tissue, and high levels of adiponectin are present in plasma [24]. The results of in vivo and in vitro studies have suggested that adiponectin may act directly on hepatic tissue and inhibit glucose production [28, 29]. Adiponectin is thought to play an important role in both glucose and lipid metabolism, and although some of the metabolic roles of adiponectin in animal models have been elucidated, little is known about its physiological regulation in humans. Serum adiponectin concentrations increase after weight loss, possibly as a result of changes in lifestyle [30], and a high TNF-α level and a low adiponectin level are important factors in determining the severity of insulin resistance [31 – 34]. Increased visceral adipose tissue is thought to cause insulin resistance and low serum adiponectin levels, and these factors are assumed to work together to cause fat to accumulate in the liver [35 – 37]. Of note, adiponectin also has important roles in anti-inflammation, insulin sensitization, and anti-atherosclerosis. Adipose tissue is the major site of endogenous adiponectin production. Hypoadiponectinemia is observed in patients with visceral obesity and insulin resistance, especially those with NASH and atherosclerosis [38 – 40]. Furthermore, Hui et al. showed that hypoadiponectinemia is a feature of NASH independent of insulin resistance [41]. Adiponectin has also been reported to have an anti-inflammatory effect in carbon tetrachloride-induced models of liver injury as well as an

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anti-fibrogenic effect [42, 43]. Additionally, experimental data suggests that adiponectin and TNF-α suppress the local synthesis of each other in adipose tissue as well as the remote function of each other in muscle in adiponectin-deficient mice [44]. These data indicate that adiponectin plays a key role in the neutralization of TNF-α. Interestingly, adiponectin also alleviated hepatomegaly, steatosis, and abnormal liver function in nonalcoholic obese ob/ob mice [45].

Nakajima, Atsushi. Insulin Resistance and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic

Chapter V

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TNF-α and NAFLD/NASH TNF-α is an important inflammatory cytokine that is overexpressed in the adipose tissues of rodent models of obesity [46]. Clinically, enhanced TNF-α expression was shown in patients with NASH, compared with patients with simple steatosis [47]. Experimental data has shown that free fatty acids induce the production of TNF-α by promoting hepatic lipotoxicity [48]. TNF-α worsens hepatic insulin resistance by activating an inhibitor of kappa B kinase (IKK-β) or c-Jun N-terminal kinase. Moreover, the antibody-mediated neutralization of TNF-α has been shown to improve NAFLD in ob/ob mice [49]. Taken together, these findings indicate that TNF-α is a critical factor in the occurrence and progression of NAFLD/NASH.

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Chapter VI

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Leptin and NAFLD/NASH Leptin, an obese gene product mainly produced from adipocytes, is also a cytokine-type hormone that regulates food intake and fat metabolism through its actions on the central nervous system [50]. Leptin receptors (Ob-R) were originally described in hypothalamic neurons, where they are involved in the regulation of food intake and body weight [51]. In the late 1990s, Potter et al. reported that activated stellate cells in cultures express leptin during hepatic fibrosis [52]. These findings led to the hypothesis that leptin plays a pivotal role in profibrogenic responses caused by hepatotoxic chemicals in the liver.

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Chapter VII

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Peroxisome ProliferatorsActivated Receptors (PPARs) and NAFLD/NASH Peroxisome proliferators-activated receptors (PPARs) play a key role in modulating hepatic triglyceride accumulation. PPARα regulates fatty acid β-oxidation. PPARα is expressed in the liver and other metabolically active tissues including striated muscle, kidney and pancreas [53, 54]. Many of the genes encoding enzymes involved in the mitochondrial and peroxisomal fatty acid β-oxidation pathways are regulated by PPARα. In particular, the acyl-CoA synthetase, the carnitine palmitoyltransferase I, the very long-chain acyl-CoA dehydrogenase and the tri-functional protein genes encoding enzymes in the mitochondrial fatty acid β-oxidation pathway are induced by PPARα [55 – 57]. The loss of expression of the PPARα gene in mice results in hepatic steatosis under conditions of increased fatty acid metabolism in the liver, such as fasting or a high-fat diet [58]. PPARα ligands can increase stearoyl - CoA desaturase-1 (SCD-1) activity, which is necessary for VLDL secretion [59]. Most of the data regarding PPARα and hepatic lipid homeostasis comes from mouse models. However, a study demonstrated that 42% of 62 patients with NAFLD had biochemical and ultrasound evidence of improvement after treatment with fenofibrate, although histological data were not collected [60]. A small controlled study of gemfibrozil versus a placebo for four weeks

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found an improvement in aminotransferase levels after gemfibrozil treatment in patients with NAFLD [61]. Further research is needed to determine the relative importance of PPARα in regulating hepatic triglyceride metabolism in humans. PPARγ increases insulin sensitivity as well as regulating triglyceride storage in adipose tissue. The net effect of these processes is to increase triglyceride storage in adipocytes, reducing the delivery of fatty acids to the liver. Liver specific PPARγ deficient mice are protected against the development of steatosis, suggesting a role for hepatic PPARγ in liver triglyceride accumulation [62, 63]. PPARγ increases insulin sensitivity by upregulating glucose transporter 4 (GLUT4) and insulin-dependent glucose transporters in adipose tissue and striated muscle [64]; it also induces the expression of c-Cbl associated protein, which is involved in insulin resistance. Furthermore, PPARγ activation attenuates the induction of suppressors of cytokine signaling 3 (SOCS3), which is involved in the development of insulin resistance [65]. PPARγ also promotes adipocyte differentiation and the expression of proteins in adipocytes involved in fatty acid uptake [66], fatty acid transport [67], and fatty acid synthesis [68]. PPARγ also increases the expression of lipoprotein lipase, an enzyme that serves to partition fat to adipocytes, limiting fatty acid flux to the liver. Similar to PPARα, PPARγ ligands upregulate SCD1 activity, promoting VLDL secretion. Other effects of PPARγ include the induction of uncoupling protein-2, which might decrease hepatic triglyceride accumulation by increasing energy expenditure [69]. PPARγ expression might also reduce hepatic inflammation by decreasing the expression of proinflammatory cytokines, such as TNFα [70].

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Chapter VIII

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Iron Overload and NAFLD/NASH There has been a great deal of interest in the role of iron in viral and non-viral hepatitis during the past few years. Iron is considered a putative element that interacts with oxygen radicals to induce liver damage and fibrosis [71]. Metabolic syndrome and hyperinsulinemia are known to be associated with increased serum ferritin, and this association may be mediated by the presence of NAFLD [71]. High rates of hyperferritinemia and increased hepatic iron stores have been demonstrated in NASH patients [72], and the removal of excess iron by repeated phlebotomy may be of therapeutic benefit for both chronic hepatitis C patients [73] and NASH patients [74]. In steatotic livers, the saturation of β-oxidation by excess free fatty acids will ultimately lead to the generation of hydrogen peroxide, which in turn can be converted to highly reactive hydroxyl radicals in the presence of free iron [75, 76]. Strong evidence from both in vitro and in vivo studies suggests that iron overload enhances oxidative stress [77, 78]. Iron can also promote fibrosis through hepatocellular necrosis (so-called sidero-necrosis) and inflammation with the activation of Kupffer cells, which release profibrogenic mediators, either as a direct fibrogenic promoter acting as a paracrine activator of hepatic stellate cells or a cofactor in fibrogenesis in conjunction with other hepatotoxins [79]. Hereditary hemochromatosis, an inborn error of iron metabolism, is the most common autosomal recessive disorder of iron metabolism and affects 1:250 – 400 individuals

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of Northern European descent [80]. Three missense mutations in the HFE gene are responsible for hereditary hemochromatosis. One of these mutations results in the substitution of tyrosine for a highly conserved cysteine residue in the HFE protein (C282Y). There are the other two mutations in the HFE gene (H63D, S65C) [81 – 83]. Hepatic iron overload is thought to be associated with HFE gene mutations [84, 85]. The significantly higher prevalence of HFE mutations in NASH patients has been reported to be a factor in the development of liver fibrosis by increasing hepatic iron deposition [86, 87], but recent studies have failed to confirm this association [88 – 91]. The mechanisms leading to the elevation in iron indices in NASH patients remains unknown. Experimental and clinical data suggest that a mild iron overload contributes to IR [92 – 94]. IR is considered to be an essential requirement for the development of NASH [95] and has been reported to cause hepatic iron overload [92]. A relation between IR and serum ferritin concentration in NASH patients has also been reported [91].

Nakajima, Atsushi. Insulin Resistance and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic

Chapter IX

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Mitochondrial Abnormalities and NAFLD/NASH Mitochondrial abnormalities have been described in liver biopsy specimens of patients with NASH [96, 97]; however, whether the observed mitochondria abnormalities are congenital or acquired remains unclear [98]. These abnormalities likely worsen with aging and adverse environmental factors, such as an abundance of highly saturated fats [99]. Mitochondrial defects are thought to be a primary cause of steatosis because of the impaired β-oxidation of fatty acids in humans with steatosis [100]. Moreover, a recent study has shown that anti-TNF antibody improves mitochondrial dysfunction in ob/ob mice [101]. Taken together, these reports indicate that inflammation derived from oxidative stress is one of the most important backgrounds in patients with NAFLD/NASH as well as metabolic syndrome.

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Chapter X

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Genetic Influences in NAFLD / NASH Although the relationship between insulin resistance, oxidative stress, inflammatory mediators and NAFLD has been described, the real mechanism responsible for the induction of steatosis and its progression to NASH remains unknown. Both genetic and environmental factors are important for the development of NAFLD. While gene mutations represent rare alterations (present in less than 1% of the population), gene polymorphisms are far more common (~ 1/500 – 1/1000 base pairs, and more than 1% of the population), with current estimates of about 1 million in the human genome. Thus, single nucleotide polymorphisms (SNPs) are a useful tool for searching for genetic factors and have been intensively investigated in NASH pathogenesis, including SNPs in genes involved in lipid metabolism, the insulin signaling pathway, oxidative stress, and inflammation; nevertheless, whether genomic variability exerts a role in the first and/or second hit promoting NASH remains unclear [102]. Part of the problem is that distinguishing genetic factors from other NASH-associated risk factors (i.e. diet, environment, etc.) is quite difficult. The selection of SNPs in studies on NAFLD is based on several factors including 1) our current knowledge of disease pathogenesis, 2) our knowledge of the gene and its function, and 3) the location of the gene within the genome (based upon linkage data). Attention has been

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mainly focused on genes related to fatty acid flux to and from the liver and their contributions to the first hit. Interleukin-6 (IL-6) is an interleukin that acts as both a proinflammatory and anti-inflammatory cytokine and is secreted by T-cells and macrophages as well as adipocytes. IL-6 (IL-6-174G/C) mutations are reportedly associated with NAFLD [103]. Angiotensin II type receptor (AGTR1) is recognized as an important factor in the etiology of liver fibrosis. An AGTR1 polymorphism (rs3772622) has been demonstrated to influence the risk of NAFLD and of liver fibrosis in NALFD [104]. The transcription factor 7-like 2 (TCFL7L2) polymorphism predisposes individuals to diabetes by modulating betacell function and is a risk factor for NAFLD and liver injury [105]. Polymorphisms of PPARs, such as PPARα (Val227Ala) [106], PPARγ (C161T) [107], and PPARγ coactivator 1 alpha (PPARGC1A) [108], are reportedly associated with NAFLD. The polymorphisms of adipocytokines, such as adiponectine (45GT and 276GT) [109], leptin receptor (G3057A) [110], and TNF-α [111] have been reported to contribute to the etiology of NAFLD. However, ethnic differences in the distributions of the genotypes of genes that have been implicated in NAFLD athogenesis might have clinical implications for the outcome of NAFLD, and Wong reported that adiponectine and TNFα gene polymorphisms were not associated with NAFLD or significant fibrosis in a Chinese population [112]. The microsomal triglyceride transfer protein (MTP) is a multifunctional heterodimeric lipid transfer protein that is expressed in the liver and participates in both the initial lipidation and subsequent neutral lipid core expansion of apolipoprotein B. Two studies have reported that polymorphisms of MTP are associated with NAFLD [113, 114]. Apolipoprotein E is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. Polymorphisms of apolipoprotein E (APOE) have been reported in subjects with NAFLD [115]. A functional polymorphism, V175M, in phosphatidylethanolamine N-methyltransferase (PEMT) has been reported to catalyze the conversion of phosphatidylethanolamine to phosphatidylcholine. A V175M variant of PEMT could be a candidate molecule determining the susceptibility to NASH [116, 117]. Beta-adrenergic receptors play an important role in the regulation of energy expenditure, and polymorphisms of the beta2- and beta3-adrenergic receptors are reportedly associated with NAFLD [118, 119].

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Genetic Influences in NAFLD / NASH

23

Several candidate genes relevant to the “second hit” have been preliminarily examined. A polymorphism in manganese superoxide dismutase (MnSOD), a gene that is important for limiting mitochondrial oxidative stress, is reportedly associated with NASH [113]. STAT3 mediates the expression of a variety of genes in response to cell stimuli and thus plays a key role in many cellular processes such as cell growth and apoptosis. The single transducer and activator of transcription 3 (STAT3) polymorphism reportedly influences disease severity [120]. Altering the circadian rhythm results in pathophysiological changes resembling metabolic syndrome and fat accumulation. The role of gene variants and the derived haplotype of the CLOCK transcription factor and their association with NAFLD and disease severity have also been investigated [121]. Methylenetetrahydrofolate reductase (MTHFR) inversely reduces 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, and a MTHFR polymorphism has been reported as a genetic risk factor for NASH [122]. The CYP2E1 enzyme is related to NASH as a result of its ability to produce reactive oxygen species, and polymorphisms of the CYP2E1 gene have been associated with liver injury in NASH [123]. Several candidate genes relevant to “fibrosis” have been preliminarily examined. A significantly higher prevalence of HFE mutations in NASH patients has been reported to affect liver fibrosis by increasing hepatic iron deposition [86, 87], but recent studies have failed to confirm this relation [88-91]. Polymorphisms of Kruppel-like factor 6 genotype [124], angiotensinogen and transforming growth factor-beta 1 (TGF-β1) [125], and angiotensin II type 1 receptor [104] have been associated with a greater degree of fibrosis in NASH patients. While these studies are interesting and provocative, further validation in larger populations is needed. In the future, genome-wide single nucleotide polymorphism scanning of cases and controls may become feasible. To date, however, studies have relied on the identification of candidate genes, case controls, and allele association methodologies.

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Chapter XI

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Therapeutic Strategy for NASH Patients NASH sometimes progresses to cirrhosis, and its prevalence is thought to be increasing because the incidences of its typical features, including fatty liver disease, obesity, and type 2 diabetes mellitus, have been increasing [126]. Evidence shows that modest and sustained weight reduction, particularly in association with exercise, not only improves aminotransferase levels and reduces steatosis, but also causes steatohepatitis to resolve and reverses hepatic fibrosis [127, 128]. Overweight and obese patients with NAFLD are generally recommended to lose 7% to 10% of their body weight through dietary modifications and exercise over the course of 6 to 12 months [129, 130]. Weight loss remains the standard of care, because no pharmacologic therapy has been conclusively demonstrated to be effective against NASH. Therefore, pharmacological therapy for NASH has elicited considerable interest. The thiazolidinedione-derivative type PPARγ-agonist pioglitazone has been reported to ameliorate insulin resistance and to improve glucose and lipid metabolism in type 2 diabetes [131]. Insulin resistance in NASH is frequently associated with chronic hyperinsulinemia, hyperglycemia, and an excessive supply of plasma free fatty acids to the liver, and thiazolidinediones reverse these abnormalities by ameliorating insulin resistance in adipose tissue [132, 133], the liver [131 – 133], and muscle [131, 134].

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Recently, the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events) has shown that pioglitazone, a thiazolidinedione that acts as an agonist of peroxisome proliferatorsactivated receptor γ (PPARγ) to ameliorate insulin resistance and improves glucose and lipid metabolism in type 2 diabetes, reduces allcause mortality, nonfatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events [135]. Interestingly, a recent prospective study has shown that histological features in patients with NASH, including hepatic steatosis, ballooning necrosis, and inflammation, are improved by the administration of pioglitazone, compared with a placebo [136]. However, fatigue and mild lower extremity edema developed in 1 out of 55 subjects who received pioglitazone. A recent randomized, double-blind study compared the effects of rosiglitazone and a placebo on steatosis and insulin sensitivity. In this so-called FLIRT (Fatty Liver Improvement with Rosiglitazone Therapy) trial, rosiglitazone improved steatosis and transaminase levels despite weight gains, an effect that was related to an improvement in insulin sensitivity [137]. Metformin is used for the treatment of type 2 diabetes, and its positive action on liver fat and insulin sensitivity has been revealed in several studies. A recent meta-analysis published in the Cochrane database showed that metformin leads to a normalization of serum aminotransferases in a significantly greater proportion of patients, compared with dietary modification (odds ratio: 2.83), and improved steatosis, as revealed by imaging (odds ratio: 5.25) [138]. Because many patients with NAFLD have severe obesity, whether bariatric surgery is suitable in this patient population is often debated in clinical practice. Over the last decade, the number of foregut bariatric surgery procedures for the treatment of obesity and its complications has been increasing, and the benefits of this procedure are becoming well established [139, 140]. The most commonly performed foregut bariatric surgery procedures include a roux-en-Y gastric bypass, adjustable gastric banding, gastroplasty, and sleeve gastrectomy [141, 142]. In general, liver histology improves significantly after foregut bariatric surgery, and the risk of further worsening is quite small [143, 144]. In a recent metaanalysis consisting of 15 studies and 766 paired liver biopsies, all the components of NAFLD showed significant improvements after foregut bariatric surgery [144]. In a pooled sampling of patients, steatosis

Nakajima, Atsushi. Insulin Resistance and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic

Therapeutic Strategy for NASH Patients

27

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improved in 93%, steatohepatitis improved in 82%, and fibrosis improved in 73%.

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Chapter XII .

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Natural History of NAFLD NAFLD can be categorized into simple steatosis and steatohepatitis (NASH). NASH is histologically progressive and can lead to cirrhosis and associated liver dysfunction. Simple steatosis has a relatively benign course but is not totally without histological consequences. For example, 4% of patients with simple steatosis reportedly develop cirrhosis and 2% suffered liver-related mortality over a median follow-up period of approximately 8 years [3]. Thus, simple steatosis is not entirely benign. Cirrhosis developed in 5% of patients with NASH in a community-based cohort and in 20% of NASH patients in a referral population [3, 145]. Recently, the association of hepatic fibrosis with obesity, insulin resistance, and hepatic steatosis has become apparent [146, 147]. The rate of cirrhosis development over a period of 10 years has been reported to be 5 – 20% in three independent studies [148 – 150]. Therefore, metabolic abnormalities might be closely associated with the progression of fibrosis. As a malignant disease, hepatocellular carcinoma (HCC) is one of the most serious diseases in patients with chronic liver disease. Recently, some epidemiological studies have reported that obesity and diabetes mellitus are risk factors for HCC [151 – 153]. NASH accounts for up to 75% of cases with cryptogenic cirrhosis, and patients with NASH and cirrhosis are at risk for hepatocellular carcinoma [HCC]. Hepatocellular carcinoma has been detected in several NASH patients, most often at the time of diagnosis and rarely during the follow-up period [145, 150]. In the relatively large Olmsted County Community Study [145], 2 out of 420 NAFLD patients developed hepatocellular carcinoma

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during a 7-year follow-up period. The estimated rate of liver-related deaths over a 10-year period was 12% for NASH patients [154 - 156].

Nakajima, Atsushi. Insulin Resistance and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic

Chapter XIII

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Conclusions In this review, we have described the current understanding of the relationships between NAFLD/NASH and insulin resistance. As we noted, numerous intricate factors are involved in the development of hepatic inflammation, steatosis/steatohepatitis, fibrosis, and carcinoma in patients with chronic liver diseases associated with metabolic syndrome. Careful attention should be given to “liver diseases,” since they likely offer a clue to elucidating the pathophysiology of so-called metabolic syndrome. To avoid the development of fatal end-stage diseases, a radical treatment strategy involving not only ordinary diet and exercise therapy but also reliable treatments for liver diseases and metabolic syndrome is needed.

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[142] Braghetto I, Korn O, Valladares H, Gutiérrez L, Csendes A, Debandi A, Castillo J, Rodríguez A, Burgos AM, Brunet L (2007). Laparoscopic sleeve gastrectomy: surgical technique, indications and clinical results. Obes. Surg. 17: 1442-50. [143] Furuya CK Jr, de Oliveira CP, de Mello ES, Faintuch J, Raskovski A, Matsuda M, Vezozzo DC, Halpern A, Garrido AB Jr, Alves VA, Carrilho FJ (2007). Effects of bariatric surgery on nonalcoholic fatty liver disease: preliminary findings after 2 years. J. Gastroenterol. Hepatol. 22: 510-4. [144] Mummadi RR, Kasturi KS, Chennareddygari S, Sood GK (2008). Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin. Gastroenterol. Hepatol. 6:1396-402. [145] Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P (2005). The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 129: 113-21. [146] Angulo P, Keach JC, Batts KP, Lindor KD (1999). Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. 30: 1356-62. [147] Dixon JB, Bhathal PS, O'Brien PE (2001). Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 121: 91-100. [148] Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ (1999). Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 29: 664-9. [149] Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS (2002). NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology. 36: 1349-54. [150] Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW (1990). The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology. 11: 74-80. [151] Caldwell SH, Crespo DM, Kang HS, Al-Osaimi AM (2004). Obesity and hepatocellular carcinoma. Gastroenterology. 127(5 Suppl 1): S97-103.

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[152] El-Serag HB, Tran T, Everhart JE (2004). Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 126: 460-8. [153] Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB (2005). Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut. 54: 533-9. [154] McCullough AJ (2004). The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin. Liver Dis. 8: 52133. [155] Hui JM, Kench JG, Chitturi S, Sud A, Farrell GC, Byth K, Hall P, Khan M, George J (2003). Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology. 38: 420-7. [156] McCullough AJ (2004). The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin. Liver Dis. 8: 52133.

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Index

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A acid, 7, 15, 16, 21, 36, 37, 41 adipocyte, 9, 16, 33 adiponectin, vii, 7, 9, 32, 33, 34, 35, 41, 42 adipose, 7, 9, 11, 16, 25, 33, 34, 36, 37, 44 adipose tissue, 7, 9, 10, 11, 16, 25, 36, 37, 44 adiposity, 34 alcohol consumption, vii alcoholic liver disease, 41 allele, 23, 43 angiotensin II, 23, 41 antibody, 11, 19, 41 apoptosis, 22, 41 assessment, 5, 32 atherosclerosis, 9 autosomal recessive, 17

B base pair, 21 benign, 1, 27 biopsy, 19 BMI, 5 body composition, 33

body fat, 37 body weight, 13, 25

C carbohydrate, 7, 32, 33 carbohydrate metabolism, 33 carbon, 9, 35 carbon tetrachloride, 9, 35 carcinoma, 27, 29 cardiovascular risk, 45 catabolism, 22 cDNA, 33 cell, 22, 37 cell line, 37 cell lines, 37 central nervous system, 13 chronic active hepatitis, 38 circadian rhythm, 22 cirrhosis, 1, 2, 25, 27, 46 cloning, 33, 35, 36 coenzyme, 36 cohort, 27, 45 complications, 2, 26 components, 26 concentration, 18, 38 control, 1, 37, 38, 40, 46 conversion, 22, 37 coronary artery disease, 34 cytochrome, 43

Nakajima, Atsushi. Insulin Resistance and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic

52

Index

cytokines, vii, 7, 16

France, 39

D defects, 19, 34 deposition, 18, 23 diabetes, vii, 5, 22, 26, 27, 31, 33, 34, 45 diabetic patients, 34, 44 diet, 15, 21, 29, 32, 44 dietary fat, 42 differentiation, 16 disorder, 17 distribution, 2, 36, 44 dyslipidemia, 1

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E encoding, vii, 15 endocrine, 33 endocrine system, 33 energy, vii, 16, 22, 33 environment, 21 environmental factors, vii, 19, 21 enzymes, 15, 36 epidemic, 31 ESR, 38 ethnicity, 43 etiology, 22 exercise, 25, 29, 44

F fasting, 1, 15, 36 fat, 1, 5, 7, 9, 13, 15, 16, 23, 26, 32, 33, 34, 35, 44 fatigue, 26 fatty acids, 7, 11, 16, 17, 19, 25, 34, 35, 36 ferritin, 18, 38 fibroblasts, 37 fibrogenesis, 17, 38 fibrosis, 1, 2, 17, 22, 23, 26, 27, 29, 31, 35, 38, 39, 43, 46 food intake, 13

G gastrectomy, 26, 45 gene, 9, 13, 15, 17, 21, 22, 35, 36, 37, 39, 40, 41, 42, 43, 44 gene expression, 37, 44 generation, 17 genes, vii, 15, 21, 22, 23 genetic factors, vii, 21 genome, 21, 23 genotype, 23, 43 glucose, vii, 1, 5, 9, 16, 25, 26, 32, 33, 34, 37, 40, 41 glucose tolerance, 32 GLUT4, 16, 37 glycosylation, 33 growth, 22, 35

H hemochromatosis, 17, 39 hepatic fibrosis, 13, 25, 27 hepatic stellate cells, 17, 36 hepatitis, 17, 31, 38, 39, 46 hepatitis d, 17 hepatocellular carcinoma, vii, 27, 46 hepatocytes, 1, 7 hepatoma, 40 hepatomegaly, 10 hepatotoxicity, 38 hepatotoxins, 17 histology, 26 HLA, 39 homeostasis, 5, 15, 41 hormone, 13, 35 human genome, 21 hydrogen, 17 hydrogen peroxide, 17 hydroxyl, 17, 38 hyperglycemia, 7, 25 hyperinsulinemia, 7, 17, 25, 34 hypertriglyceridemia, 37, 43

Nakajima, Atsushi. Insulin Resistance and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic

Index hypothesis, 1, 13

I identification, 23 IL-6, 21 in vivo, 9, 17, 32, 38, 44 Indians, 39 induction, 16, 21 inflammation, 1, 9, 16, 17, 19, 21, 26, 29 inflammatory mediators, 21 inhibitor, 7, 11 injury, iv, 9, 22, 23, 43 interactions, vii, 33 iron, 17, 23, 38, 39, 40

K kidney, 15

metabolic syndrome, vii, 2, 5, 19, 23, 29, 32, 37 metabolism, vii, 1, 13, 15, 17, 34, 37 metabolizing, 36 metformin, viii, 26, 44 MHC, 39 mice, 10, 11, 15, 16, 19, 35, 36, 37, 41 mitochondria, 19 model, 5, 32 models, 9, 11, 15 morbidity, 2 mortality, 2, 26, 27 myocardial infarction, 26

N necrosis, 17, 26, 33, 42 neurons, 13 nutrients, vii

O

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L leptin, vii, 7, 13, 22, 32, 33, 36, 37 lifestyle changes, 33 lipid metabolism, 1, 9, 21, 25, 26 lipolysis, 7 liver, vii, 1, 5, 7, 9, 13, 15, 16, 17, 19, 21, 22, 23, 25, 26, 27, 29, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 liver cirrhosis, vii, 2 liver damage, 17 liver disease, vii, 1, 25, 27, 29, 31, 32, 35, 37, 38, 39, 40, 41, 42, 43, 45, 46 liver failure, vii, 1 lysine, 33

M macrophages, 22, 35 management, 2, 45 manganese, 22, 42 meta-analysis, 26, 45

53

obesity, 2, 5, 9, 11, 25, 26, 27, 31, 32, 33, 34, 35, 45 overload, 17, 38, 39, 40 oxidation, 15, 17, 19 oxidative stress, 17, 19, 21, 22, 38 oxygen, 17

P pancreas, 15 pathogenesis, vii, 7, 21, 32 pathophysiology, viii, 3, 29 pathways, vii, 15 phlebotomy, 17, 38, 40 phosphatidylcholine, 22 phosphatidylethanolamine, 22, 42 pilot study, 38, 44 pioglitazone, 25, 44, 45 placebo, 15, 26, 45 plasma, 9, 25, 37, 38, 41 plasminogen, 7 polymorphism, 22, 23, 41, 42

Nakajima, Atsushi. Insulin Resistance and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic

54

Index

polymorphisms, vii, 21, 22, 23, 41, 42, 43 population, 2, 21, 22, 26, 27, 42, 45, 46 portal vein, 7 production, 1, 9, 11, 34 pro-inflammatory, 21 promoter, 17, 36, 42 proteins, 16

R

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reactive oxygen, 23 receptors, vii, 13, 15, 22, 35, 36, 37, 38, 41 reciprocal relationships, 2 regulation, 9, 13, 22, 32, 33, 37 resistance, vii, 1, 2, 5, 7, 9, 16, 25, 32, 40 risk, 2, 21, 22, 23, 26, 27, 31, 46 risk factors, 2, 21, 27, 31, 46 rosiglitazone, 26, 44

S sampling, 26 saturated fat, 19 saturation, 17 secretion, 15, 16 sensitivity, 5, 16, 26, 32 serum, 9, 17, 26, 33, 34, 38 serum ferritin, 17 severity, 5, 9, 22, 31, 32, 39 skeletal muscle, 37 spectrum, vii, 1, 31 storage, 1, 16 stress, 21, 38 substitution, 17, 41 susceptibility, 22, 41, 42 syndrome, 5, 17, 29, 32, 40 synthesis, 7, 9, 16

T TGF, 23 therapy, 25, 29, 34, 44 thiazolidinediones, viii, 25 tissue, 7, 9, 16, 36 TNF, v, vii, 7, 9, 11, 16, 19, 22, 35, 41 TNF-alpha, 35 transcription, 22, 33, 43 transforming growth factor, 23 transport, 16, 37 trial, 26, 33, 37, 44, 45 triglycerides, 1, 37 tumor, 7, 35, 38, 42 tumor necrosis factor, 7, 35, 38, 42 type 2 diabetes, 2, 5, 25, 26, 34, 40, 41, 44, 45 tyrosine, 17

U United States, 31, 43, 46 urban population, 43

V very low density lipoprotein, 1 virus infection, 38 visceral adiposity, 32 VLDL, 1, 15, 16

W weight gain, 26 weight loss, 9, 32, 33 weight reduction, 25 women, 33, 43

Nakajima, Atsushi. Insulin Resistance and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic