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DOI 10.1002/mnfr.201300522

REVIEW

Chemoprevention of nonalcoholic fatty liver disease by dietary natural compounds Min-Hsiung Pan1,2 , Ching-Shu Lai1 , Mei-Ling Tsai3 and Chi-Tang Ho4∗ 1

Institute of Food Science and Technology, National Taiwan University, Taipei, Taiwan Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan 3 Department of Seafood Science, National Kaohsiung Marine University, Kaohsiung, Taiwan 4 Department of Food Science, Rutgers University, New Brunswick, NJ, USA 2

Nonalcoholic fatty liver disease (NAFLD) refers to a wide spectrum of liver disease that is not from excess alcohol consumption, but is often associated with obesity, type 2 diabetes, and metabolic syndrome. NAFLD pathogenesis is complicated and involves oxidative stress, lipotoxicity, mitochondrial damage, insulin resistance, inflammation, and excessive dietary fat intake, which increase hepatic lipid influx and de novo lipogenesis and impair insulin signaling, thus promoting hepatic triglyceride accumulation and ultimately NAFLD. Overproduction of proinflammatory adipokines from adipose tissue also affects hepatic metabolic function. Current NAFLD therapies are limited; thus, much attention has been focused on identification of potential dietary substances from fruits, vegetables, and edible plants to provide a new strategy for NAFLD treatment. Dietary natural compounds, such as carotenoids, omega-3PUFAs, flavonoids, isothiocyanates, terpenoids, curcumin, and resveratrol, act through a variety of mechanisms to prevent and improve NAFLD. Here, we summarize and briefly discuss the currently known targets and signaling pathways as well as the role of dietary natural compounds that interfere with NAFLD pathogenesis.

Received: July 19, 2013 Revised: September 25, 2013 Accepted: October 9, 2013

Keywords: Chemoprevention / Nonalcoholic fatty liver disease / Dietary natural compounds

1 Correspondence: Dr. Min-Hsiung Pan, Institute of Food Science and Technology, National Taiwan University, No.1, Section 4, Roosevelt Road, Taipei 10617, Taiwan E-mail: [email protected] Fax: +886-2-33661771 Abbreviations: ␣-SMA, ␣-smooth muscle actin; ACC, acetylcoenzyme A carboxylase; ACO, acyl-coenzyme A oxidase; ALT, alanine aminotransferase; AMPK, AMP-activated protein kinase; AST, aspartate aminotransferase; CAT, catalase; CPT-1, carnitine palmitoyl transferase 1; CYP, cytochrome P450; DHA, docosahexaenoic acid; DR5, death receptor 5; EGCG, epigallocatechin3-gallate; EPA, eicosapentaenoic acid; FA, fatty acid; FAS, FA synthase; FFA, free FA; FOXO, forkhead box protein O; G6Pase, glucose 6-phosphatase; GPx, GSH peroxidase; GSH, glutathione; GST, GSH S-transferase; HFD, high-fat diet; HMG-CoA, 3hydroxy-3-methylglutaryl-coenzyme A; HSC, hepatic stellate cell; HSL, hormone-sensitive lipase; IRS-1, insulin receptor substrate 1; JNK, c-Jun N-terminal kinase; LDL, low-density lipoprotein; MCP-1, monocyte chemotactic protein 1; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NF-␬B, nuclear factor-␬B; Nrf2, NF-E2-related factor 2; PEPCK, phosphoenolpyruvate carboxykinase; PI3K, phosphatidylinositol-3 kinase; PPAR, peroxisome proliferator-activated receptor; Pten, phosphatase and tensin homolog; ROS, reactive oxygen species; SCD1, stearoyl-CoA desaturase 1; SFAs, saturated FAs; SIRT, sirtuin;  C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Introduction

Nonalcoholic fatty liver disease (NAFLD) has emerged as a common liver disorder that is characterized by abnormal hepatic triglyceride (TG) accumulation in the absence of excessive alcohol consumption. This disease represents a histological spectrum ranging from simple hepatic steatosis (defined as hepatic TG >5% by liver weight) that can progress to inflammatory nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and ultimately end-stage liver failure or hepatocellular carcinoma [1]. Simple hepatic steatosis is a benign process without inflammation, whereas lobular inflammation and hepatocellular injury followed by fibrosis are common in NASH and are believed to drive progression to cirrhosis [2]. Liver biopsies are currently the gold standard for NASH clinical diagnosis and staging because there are no specific symptoms to distinguish this disease. Other clinical diagnostic SOCS, suppressor of cytokine signaling; SOD, superoxide dismutase; SREBP-1, sterol regulatory element binding protein 1; TF-1, theaflavin; TG, triglyceride; TGF-␤1, transforming growth factor ␤1; TNF-␣, tumor necrosis factor ␣; UCP, uncoupling protein; VLDL, very-low-density lipoprotein ∗ Additional corresponding author: Dr. Chi-Tang Ho, E-mail: [email protected]

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indices include increased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), elevated BMI, and metabolic syndrome [1, 3]. NAFLD prevalence has increased worldwide in the past 20 years, reflecting its emergence as a major public health problem. Epidemiological studies demonstrated that NAFLD prevalence is different and varies wildly depending on population and diagnostic methods or definition [4]. Population studies estimate that approximately 25–30% of the general population in the United States [5,6] and 13–60% of the population from Japan, Italy, China, and Korea have NAFLD [7–10]. The increasing NAFLD prevalence is not only in adults, but also in children (3–10%) and is rising up to 40–70% among obese children [11]. Although NASH is the most serious form of NAFLD, it is difficult to diagnose without a liver biopsy, which results in less population-based prevalence studies. Previous epidemiological research demonstrated that approximately 30% of simple steatosis cases progress to NASH in NAFLD patients, and approximately 20% of NASH patients develop cirrhosis. Once developed, 30–40% of cirrhosis patients succumb to liver-related death over a 10-year period [12]. NASH patients had increased cardiovascular disease and liver-related disease-induced mortality compared to simple steatosis patients. Most of these patients were diagnosed with diabetes or impaired glucose tolerance and had increased weight gain [13]. Previously, researchers suggested a number of risk factors implicated in NAFLD, including age, race, genetics, and chronic infection, and NAFLD was also strongly associated with metabolic conditions, such as obesity, type 2 diabetes, hypertension, and dyslipidemia, which are regarded as hepatic manifestations of metabolic syndrome [3, 4].

2

NAFLD pathogenesis

The liver is a necessary and important organ for whole body metabolism and energy homeostasis. Hepatic TG accumulation is a hallmark of NAFLD that results from several sources, including increased free fatty acid (FFA) delivery from adipose tissue (as lipolysis), dietary fatty acids (FAs), elevated hepatic de novo lipogenesis, reduced very-low-density lipoprotein (VLDL) export, and decreased FA ␤-oxidation. Except for hepatic steatosis, other histological and biological changes associated with NAFLD include lobular and portal inflammation, hepatocyte ballooning and apoptosis, increased AST levels, collagen deposition, and hepatic fibrosis [6]. This process also involves hepatocyte lipotoxicity, increased oxidative stress from mitochondrial ␤-oxidation, inflammatory cytokine release, and immune cell and hepatic stellate cell (HSC) activation. A classic two-hit model has been proposed to explain NAFLD pathogenesis by Day and James in 1998 [14]. The first hit refers to hepatic TG accumulation (steatosis) that increases liver sensitivity to a variety of second hits, such as inflammatory cytokines and oxidative stress that cause hepatic injury, necroinflammation, and fibrosis. However, this hypothesis has been challenged because some  C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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steatosis patients develop NASH without implicating secondhit but other external injury. A number of in vitro and in vivo epidemiological studies strongly suggest that obesity and hepatic insulin resistance are critical pathogenic factors in NAFLD. Dysfunctions in these signaling and regulation mechanisms impair hepatocellular functions and predispose patients to NAFLD pathogenesis. Although the precise mechanisms for NAFLD development and progression remain incompletely understood, NAFLD is currently recognized as a consequence of a multihit hypothesis, involving obesity, insulin resistance, oxidative stress, and proinflammatory processes [15].

2.1 Obesity and adipokines Obesity is defined as excessive fat accumulation in adipose tissue and it is associated with numerous metabolic diseases such as cardiovascular disease, type 2 diabetes, and NAFLD [10,16]. Several population studies demonstrated that the prevalence of simple steatosis, NASH, and NAFLD was increased in overweight and obese individuals [10,17–20]. High NASH and NAFLD prevalence also occurred in severely and morbidly obese individuals, indicating that its incidence is highly associated with the degree of obesity [21–23]. Moreover, NAFLD was also found in obese insulin-resistant children and those with elevated serum ALT levels [24, 25]. As caloric intake increases, adipocytes store energy in the form of TGs that result in enhanced adipogenesis, increased adipose tissue mass, and consequently obesity [26]. Insulin inhibits adipose tissue lipolysis by lowering cyclic adenosine monophosphate levels and activating phosphodiesterase 3b, thereby attenuating protein kinase A activity and decreasing protein kinase A dependent hormone-sensitive lipase (HSL) activation, or through dephosphorylation of HSL at regulatory and basal phosphorylation sites by protein phosphatase [27, 28]. FFAs released from adipose tissue by enhanced TG hydrolysis via insulin resistance-mediated HSL increases resulted in elevated plasma FFAs. Subsequently, these FFAs are transported to the liver via the hepatic artery and portal vein and thus increase hepatic FFA influx. Increased FFAs delivered to the liver from visceral adipose tissue induce hepatic insulin resistance via reduced hepatic insulin clearance and increased circulating insulin levels, which decreases insulinstimulated glucose uptake through IRS-1-associated (where IRS-1 is insulin receptor substrate 1) phosphatidylinositol3 kinase (PI3K) signaling impairment and reduced insulinmediated hepatic glucose output suppression and endogenous glucose production [29–31]. FFAs also stimulate hepatic gluconeogenesis and TG synthesis and directly cause hepatic lipotoxicity, which promote NAFLD pathogenesis. One study demonstrated the contribution of the FFA source in NAFLD patients using multiple stable isotope techniques. Of the hepatic TG, 59% was from serum nonesterified FAs, 26% was derived from hepatic de novo lipogenesis, and only 15% was from dietary sources [32]. This study suggested www.mnf-journal.com

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that although increased FFAs from other pathways also account for hepatic lipid accumulation, elevated FAs from peripherally expanded adipose tissue and de novo lipogenesis are the major sources of hepatic and lipoprotein fat accumulation in NAFLD. Fat distribution may also be more important than total adipose tissue mass in obesity [33]. Visceral adipose tissue is strongly associated with metabolic complications including hepatic steatosis [34, 35] and contributes to hepatic inflammation and fibrosis in NAFLD patients [36]. Compared with subcutaneous adipose tissue, visceral adipose tissue increases insulin resistance, metabolic activity, lipogenesis, and lipolysis [37, 38]. Deregulated adipokine secretion from adipose tissue is another mechanism by which obesity is involved in NAFLD via impaired insulin signaling and proinflammatory properties. Most adipokines are increased in obese adipose tissue, and some of these have been linked to insulin resistance, such as tumor necrosis factor-␣ (TNF-␣), leptin, and IL-6 [39]. Visceral adipose tissue-generated adipokines directly transported to the liver and cause harmful effects on hepatocytes. Obesity is significantly associated with chronic low-grade inflammation and insulin resistance, which is first evidenced by TNF-␣ release from adipocytes [40]; in addition, using TNF-␣ neutralizing antibodies improves insulin resistance. TNF-␣ knockout mice or its receptor have ameliorated insulin resistance in both diet-induced obese and leptin-deficient (ob/ob) mice that develop severe type 2 diabetes and hypercholesterolemia [41]. Clinical studies demonstrated that both serum and hepatic TNF-␣ is increased in NASH patients compared with simple steatosis patients, and the increased TNF-␣ levels are correlated with the severity of histological changes [42–44]. Inhibition of endogenous TNF-␣ production improved steatosis, steatohepatitis, and insulin resistance in NASH patients as well as both HFD-fed (where HFD is high-fat diet) and leptin-deficient (ob/ob) mice [45–47]. These studies reveal the role of TNF-␣ in insulin signaling impairment in NAFLD. At the molecular level, increased TNF-␣ is observed by FFA treatment of mouse hepatocytes, which downregulates insulin receptor phosphorylation and thus blocks insulin signaling [48, 49]. FFA exposure also caused hepatocyte lipotoxicity by promoting TNF-␣ production and, thus, I␬B kinase ␤/nuclear factor-␬B (NF-␬B) activation, resulting in abundant proinflammatory cytokine expression [48]. TNF-␣ also stimulated hepatic FA synthesis and increased serum TG levels [50]. IL-6 is another proinflammatory cytokine that is produced from visceral adipose tissue and with systemic effects on the immune response. Increased IL-6 is found in obese patients, is decreased by weight loss [51, 52], and is a predictor of insulin resistance [53]. Secreted IL-6 levels from abdominal adipose tissue are higher than that from subcutaneous adipose tissue [54]. In severely obese patients, IL-6 and TNF-␣ mRNA expression in both subcutaneous and visceral adipose tissue is more than 100-fold greater than liver tissue [51]. Visceral adipose tissue-derived IL-6 enters the liver; therefore, the liver might be a major IL-6 target organ. Several studies suggested that IL-6 caused hepatic insulin resistance by  C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

inhibiting receptor autophosphorylation, IRS-1 phosphorylation, and downstream PI3K/Akt signaling via suppressor of cytokine signaling (SOCS) 3 activation [51, 55]. An HFD animal study also demonstrated that adipose tissue-derived IL-6 increased hepatic SOCS3 expression followed by reduced insulin-stimulated AKT activation and consequent hepatic insulin resistance [56]. Leptin is mainly produced by adipocytes and is an important adipokine in the regulation of energy expenditure, food intake, energy balance, and the immune system [57, 58]. Increased serum leptin levels are found in NAFLD patients [59, 60] and are correlated with hepatic steatosis severity, but not with inflammation or fibrosis [61, 62]. Comparatively, a 6-month follow-up study revealed no association between serum leptin levels and NAFLD severity [63]. Leptin-deficient (ob/ob) mice develop obesity, fatty liver, and insulin resistance [64]. Although there is no correction of leptin and hepatic fibrosis in human studies, much evidence suggests that leptin is a fibrogenic factor that is implicated in hepatic fibrosis. Leptin is essential for HSC activation and transforming growth factor ␤1 (TGF-␤1) production that promotes collagen synthesis and is involved in hepatic fibrosis [65,66]. However, an in vitro study demonstrated that the fibrogenic effect of leptin and HSC activation is because of interactions with hepatic Kupffer cells but not direct effects on HSC [67]. Adiponectin is an anti-inflammatory adipokine that is also produced by adipocytes and is suggested to inhibit NAFLD [43, 68]. Decreased adiponectin is observed in NASH patients compared with simple steatosis and is associated with more extensive hepatic necroinflammation [43]. Increased levels of TNF-␣ and IL-6, two major proinflammatory adipokines, inhibit adiponectin expression [69]. Adiponectin inhibits NAFLD and exerts a hepatoprotective effect through multiple mechanisms, including suppression of steatosis, fibrosis, inflammation, lipotoxicity, and an increase in insulin sensitivity and as has been described in recent reviews [70, 71]. Recombinant adiponectin significantly attenuated hepatomegaly, steatosis, and hepatic inflammation in leptin-deficient (ob/ob) mice and cultured hepatocytes via enhancement of hepatic FA oxidation and reduced FA synthesis as well as TNF-␣ production [72, 73].

2.2 Insulin resistance Insulin signaling is essential for carbohydrate and lipid metabolism in various organs and tissues and is crucial for homeostatic regulation of blood glucose levels by the liver [74]. In physiological states, pancreatic ␤ cells secrete insulin in response to increased blood glucose levels after feeding. Insulin stimulates hepatic glucose uptake and conversion of glucose into glycogen, TG synthesis, and export to adipose tissue as VLDL. This biological function of insulin is triggered by insulin binding to the insulin receptor and activation of the intracellular signaling cascade. Once bound, the insulin receptor ␤-subunit with tyrosine kinase www.mnf-journal.com

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activity phosphorylates IRS family members, further activating various signaling pathways that are involved in the metabolic effects of insulin [75], which involves downstream targeted insulin/IRS and PI3K/Akt pathway activation. PI3Kmediated Akt activation is important for glucose transport, glycogen and protein synthesis as well as hepatic gluconeogenesis suppression. Akt-dependent forkhead box protein O (FOXO) transcription factor phosphorylation results in their exclusion from the nucleus to the cytoplasm, thus blocking the DNA binding ability of FOXOs and subsequent downstream gluconeogenic gene transcription including genes, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) [75, 76]. Akt also promotes translocation of glucose transporter 4 to cell membranes together with the Cbl/Tc10 pathway that facilitates glucose uptake [77] and subsequently reduces hepatic gluconeogenesis and blood glucose levels. In addition to regulating hepatic glucose metabolism, insulin signaling stimulates hepatic de novo lipogenesis through sterol regulatory element binding protein 1 (SREBP-1) transcription factor activation that upregulates acetyl-coenzyme A carboxylase (ACC) and FA synthase (FAS) [78]. Insulin resistance is a physiological condition that is described as decreased target cell sensitivity to the normal insulin concentrations and, hence, insulin-mediated uptake and glucose utilization in insulin-sensitive organs and tissue including the liver, adipose, and muscle tissue. Insulin resistance has been linked to metabolic syndrome and is a major cause of type 2 diabetes because of pancreatic ␤ cell dysfunction [79]. Extensive research also has highlighted the implication of insulin resistance in NAFLD. Increased NAFLD prevalence is found in patients with impaired glucose tolerance or diagnosed diabetes [10, 25, 80]. A study of type 2 diabetic patients demonstrated that NAFLD is extremely common in type 2 diabetes patients with 69.5% prevalence [81]. A population-based matched retrospective cohort study also demonstrated that a higher risk of advanced liver disease is found in newly diagnosed diabetic individuals compared with those who do not have type 2 diabetes [82]. Moreover, insulin resistance is associated with the degree of NAFLD, advanced fibrosis, and mortality [83, 84]. The mechanism underlying hepatic insulin resistance is poorly understood, but may involve FFA overflow, proinflammatory adipokines, hyperinsulinemia, hyperglycemia, and adipose tissue insulin resistance. Insulin signaling inactivates adipose tissue HSL to suppress lipolysis, whereas adipose tissue insulin resistance results in increased hepatic FFA influx and further lipid accumulation [27, 28]. It has been demonstrated that in HSL knockout mice, hepatic insulin sensitivity is increased by reducing TG concentrations [85]. Increased FFAs also contribute to hepatic insulin resistance as described above (Section 2.1). FFAs and proinflammatory adipokines, such as IL-6 and TNF-␣, from adipose tissue impaired hepatic insulin signaling via c-Jun N-terminal kinase (JNK), I␬B kinase/NF-␬B, and SOCS protein activation, resulting in IRS inactivation or degradation [86, 87]. High  C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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glucose-induced hyperinsulinemia in blood caused hepatic SREBP-1 activation and promoted hepatic de novo lipogenesis [88]. This hyperinsulinemia also inhibited FFA oxidation by upregulating malonyl-CoA levels, resulting in carnitine palmitoyl transferase 1 (CPT-1) inhibition, thus decreasing FA shuttling into mitochondria and reduced hepatic lipid utilization [89, 90]. The pathogenic role of insulin resistance in NAFLD is complicated by the involvement of multiple factors and molecules between organs that amplify deregulated signaling cascades and thus alter hepatic gene expression as well as glucose and lipid metabolism.

2.3 Lipotoxicity and lipoapoptosis Accumulation of FFAs and their metabolites causes cell damage and death known as lipotoxicity and lipoapoptosis. Indeed, apoptosis is a prominent feature of NASH that correlates with histological hepatic inflammation and fibrosis [91]. As mentioned before, hepatic TG accumulation per se does not directly cause hepatotoxicity, whereas FFAs and a wide range of lipid metabolites potently cause lipotoxicity and lipoapoptosis. FFAs cause lipotoxic effects through various mechanisms, including lysosomal destabilization, mitochondrial pathways, death receptor signaling, and ER stress. FFA exposure in mouse hepatocytes causes Bax translocation to lysosomes and lysosomal destabilization with lysosomal cysteine protease (cathepsin B) release that contributes to loss of lysosomal integrity. Downregulating Bax and inhibiting lysosomal permeabilization reduced FFA-induced toxicity [92]. FFA treatment decreased Bcl-xL, which is an anti-apoptotic BCl-2 family protein, while overexpression blocked lysosomal permeabilization and apoptosis [92]. FFAs also caused NF␬B-dependent TNF-␣ expression that may further promote insulin resistance and hepatic lipogenesis [48, 93]. A recent study found that saturated FAs (SFAs) induced cytotoxicity and apoptosis both in human and mouse hepatocytes, but MUFAs only resulted in lipid accumulation [94]. SFAs such as palmitate and stearic acid trigger hepatic lipoapoptosis via Bim activation, which is a BH3 domain-only protein that further binds to Bax and triggers mitochondrial apoptosis pathways [95]. Pharmacological and genetic JNK inhibition or Bim knockdown by siRNA both attenuated SFA-induced cell death [95]. A further study demonstrated that FFAs mediated protein phosphatase 2A-dependent FOXO3a dephosphorylation that in turn stimulated FoxO3a-dependent Bim expression and hepatocyte apoptosis [96]. Elevated Fas receptor (CD95) expression occurred in liver specimens from NASH patients and correlated with disease severity [97]. In carbohydrate-fed mice, hepatocyte Fas expression was increased and accompanied by hepatic steatosis [98,99]. Fas agonist administration increased hepatocyte apoptosis and liver injury in diet-induced obese mice [98]. Upregulated Fas expression was noted in FFA-treated HepG2 cells and increased the sensitivity to Fas agonist-induced apoptosis [98]. FFA treatment of hepatocytes caused JNK-dependent TNF-related www.mnf-journal.com

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apoptosis-inducing ligand receptor death receptor 5 (DR5) upregulation and sensitization to TNF-related apoptosisinducing ligand mediated apoptosis [100]. Increased DR4 and DR5 expression was also demonstrated in livers from human NASH patients [100,101]. A recent study suggested that FFAinduced DR5 expression was transcribed by C/EBP homology protein (CHOP), an ER stress-mediated transcription factor. This study also suggested that FFAs induced lipoapoptosis by promoting DR5 clustering and lipid raft redistribution within the plasma membrane [102]. These studies indicated that DR upregulation during steatosis increased hepatocyte susceptibility to apoptosis through other mechanisms. Cellular lipid accumulation also induces ER stress. Hepatocyte FFA exposure disrupts ER homeostasis, induces ER stress, and promotes apoptosis [103]. Mice fed a high saturated fat diet had hepatic steatosis and increased ER stress via spliced X-box binding protein 1, upregulated glucose-regulated protein 78 levels and increased hepatic apoptosis [104]. Eukaryotic initiation factor-2␣ phosphorylation and increased levels of both glucose-regulated protein 78 and X-box binding protein 1 were observed in NAFLD and diet-induced NASH patients [105,106]. Upregulation of these signaling molecules is linked to lipid accumulation, insulin resistance, and hepatic inflammation via JNK, NF-␬B, and reactive oxygen species (ROS) production [107].

2.4 Oxidative stress Oxidative stress is a redox imbalance that results from excessive ROS or free radicals and decreased antioxidant defense. Elevated free radicals, increased DNA damage, and lipid peroxidation as well as reduced antioxidants have been observed in NAFLD patients [108, 109]. In addition to the direct hepatotoxic effect, FFA overload induces ROS production via mitochondrial dependent ␤-oxidation or microsomal enzymes. Increased hepatic microsomal FA oxidizing enzyme cytochrome P450 (CYP) 2E1 was found in mice with diet-induced hepatic steatosis and NASH patients and is considered to be a source of ROS [110, 111]. Mitochondrial ␤-oxidation is regulated by CPT-1, while FFAs induce peroxisome proliferator-activated receptor (PPAR) ␣ to up-regulate CPT-1 expression [112]. ROS overproduction causes an attack on DNA, protein, and cellular membranes, which induces lipid peroxidation and results in mitochondrial dysfunction that contributes to hepatocellular damage. Mitochondrial abnormalities include ultrastructural lesions, mitochondrial DNA depletion, impaired ATP synthesis, and decreased respiratory chain complex activity are associated with NAFLD and might result in further ROS production [113, 114]. TNF␣ is also involved in mitochondrial dysfunction through induction of mitochondrial swelling and interference among mitochondrial respiratory chain complexes [115, 116]. PUFA peroxidation induced apolipoprotein B100 degradation, a critical protein component of VLDL; thus, decreased VLDL secretion may be relevant to hepatic lipid accumulation [117].  C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Moreover, Cu/Zn superoxide dismutase (SOD), glutathione (GSH) peroxidase (GPx), and catalase (CAT) activities are increased in NAFLD patients compared with simple steatosis, reflecting the state of oxidative stress [118].

2.5 Hepatic inflammation NASH is an extreme form of NAFLD and has gotten more attention recently because it can progress to fibrosis and cirrhosis. NASH is characterized by steatosis with mixed lobular inflammation and hepatocyte ballooning with or without fibrosis [2,119]. Other features are also included such as portal inflammation or panacinar steatosis, which are associated with advanced liver fibrosis [119, 120]. Hepatic inflammation is a complicated condition that is caused by various factors, including FFAs, cytokines, adipokines, and oxidative stress that results in hepatocellular injury, further inflammatory cell recruitment, which releases various oxidants and proinflammatory molecules, and HSC activation, which is involved in hepatic fibrosis [2]. The major source of hepatic TNF-␣ and IL-6 is derived from injured hepatocytes, immune cells, and activated Kupffer cells. Increased TNF-␣ activates JNK signaling and results in hepatocyte apoptosis [121]. Studies have revealed that NF-␬B and JNK activation are essential for inflammatory cell recruitment in NASH [122, 123]. A recent study demonstrated that hepatocytes release danger signals leading to activation of mononuclear cells and production of IL-1␤ and TNF-␣ after FFA exposure [124]. The role of IL-6 in liver pathology is very complicated because it is considered to have hepatoprotective effect and promote liver regeneration. Although the way IL-6 participates in NAFLD is still unclear, studies have suggested a positive correlation between hepatic IL-6 and degree of disease. Increased IL-6 expression in hepatocytes is found in patients with NASH and correlated to degree of inflammation, stage of fibrosis, and systemic insulin resistance [125]. Blockade of IL-6 signaling by neutralizing antibody against the IL-6 receptor (MR16–1) enhanced hepatic steatosis but improved hepatic injury in mice fed with an methionine choline-deficient diet [126]. Overproduction of cytokines, such as TGF-␤ by Kupffer cells, infiltrating inflammatory cells, and fibroblasts triggers HSC activation and differentiation into myofibroblast-like cells, promotes collagen synthesis and blocks extracellular matrix degradation by enhancing tissue inhibitors of matrix metalloprotease expression [127]. Furthermore, adipose tissue-generated leptin increased the collagen I and III production in HSCs via a JAK- and PI3K-mediated pathway [128]. In rats with diet-induced steatohepatitis, hepatocytes are the source of lipid peroxidation at early stages followed by hepatocellular injury, further inflammatory cell recruitment, and HSC activation [129]. Activation of Kupffer cells and other inflammatory cells also generates ROS through NADPH oxidase [130, 131]. Although oxidative stress may not initiate hepatic inflammation, ROS overproduction could cause hepatocyte damage or death and, in turn, cytokine release that www.mnf-journal.com

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provides positive feedback on inflammatory signaling and promotes NASH pathogenesis.

3

Molecular mechanism of dietary natural compounds used to treat NAFLD

Development and progression of NAFLD and NASH is a multifactorial process. Despite understanding the process and mechanism, there is no established treatment or therapy for NAFLD. Epidemiological studies suggested a combination of lifestyle interventions, such as decreased caloric intake, altered dietary composition, weight loss and physical exercise, is safe and effective for improving obesity-mediated insulin resistance and NAFLD [132]. Current pharmaceutical drugs, such as insulin-sensitizers, thiazolidinediones, statins, antioxidants, and Omega-3 PUFAs, which targeting the mechanisms involved in metabolic syndrome have been evaluated in animal and clinical studies [132,133]. However, some of these therapeutic agents tested in patients with limited findings and inconsistent outcomes, and because of short durations and randomized trails, some of these have safety concerns [134, 135]. Evidence has supported the concept that NAFLD is associated with diet-associated obesity and insulin resistance. This evidence also offers novel targets for NAFLD intervention and treatment by dietary and nutritional components. Currently, researchers have become increasingly interested in searching for natural products from dietary and herbal plants that can both prevent and control NAFLD via a chemopreventive strategy. Many dietary natural compounds isolated from fruits, vegetables, and edible plants reportedly possess health-promoting properties, such as anti-inflammation, antioxidation, antiobesity, and increased insulin sensitivity. Furthermore, in vivo and in vitro studies demonstrated that many herbal plants have been used for management of fatty liver conditions and improvement of NAFLD by their hypoglycemic, antihyperlipidemic, and hepatoprotective effect, and without major side effect [133]. Convincing scientific evidence in animal and human studies displays the potential of these dietary natural compounds for NAFLD treatment. Understanding the regulatory role and mechanism of these dietary natural compounds may help to prevent and treat NAFLD. The chemopreventive effects and molecular targets of selected dietary natural compounds in NAFLD are highlighted below (Table 1).

3.1 Carotenoids Carotenoids are fat-soluble pigments and potent antioxidants that are rich in many plants, fruits, and flowers. Lycopene is a member of the carotenoid family, with a highly unsaturated 40-carbon molecule that contains 11 conjugated and two unconjugated double bonds. The main sources of lycopene are tomato, watermelon, papaya, and orange grapefruit. Rats administered 2 and 4 mg/kg lycopene for 6 wk  C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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displayed reduced serum ALT and AST activities and TG and cholesterol levels. Hepatic steatosis and inflammation were also reduced, followed by decreased lipid peroxidation and increased GSH as well as lowered serum TNF-␣ [136]. In a NASH-promoted hepatocarcinogenesis animal study, dietary lycopene reduced HFD- and diethylnitrosamine-induced hepatic precancerous lesions. This inhibitory effect is associated with decreased hepatic lipid peroxidation, NF-␬B levels, and upregulation of both nuclear NF-E2-related factor 2 (Nrf2) and its target gene heme oxygenase 1. Increased lycopene levels are found in HFD-fed but not control diet-fed rat livers, indicating that lycopene is incorporated into micelles along with dietary fat and that it has efficacy in target organs [137]. Dietary lycopene feeding in gerbils also restored HFD-induced decreased liver antioxidant enzyme defenses, including CAT, GSH reductase, and GSH S-transferase (GST) activities [138]. These studies suggested that lycopene has potent antioxidative activity by alleviating oxidative stress and upregulating antioxidants to prevent HFD-induced NAFLD. In addition to the antioxidative property, a recent study demonstrated that lycopene decreased HFD-induced hepatic steatosis and FFAinduced lipid accumulation in hepatocytes via microRNA-21dependent FA-binding protein 7 inhibition [139]. ␤-Carotene is one of the most abundant carotenoids and antioxidants in vegetables and fruits. ␤-Carotene consumption is distributed in a variety of tissues including liver and adipose tissues [140]. 3T3-L1 adipocytes treated with ␤-carotene have reduced TNF␣-mediated ROS production and restored adiponectin and glucose transporter 4 production that may improve insulin resistance [141]. ␤-carotene supplementation decreased retinol deficiency-induced hepatic lipid peroxidation and enhanced CAT and GST activities, thus reducing hepatic oxidative stress [142]. Similar to lycopene, ␤-carotene acts as an antioxidant in liver or modulates adipokine production from adipose tissue to display indirect effects against NAFLD. Lutein is also a common carotenoid that is found in most fruits and vegetables that reduces hepatic free cholesterol, lipid peroxidation, and TNF-␣ because of decreased NF-␬B p65 DNA binding activity in high cholesterol diet-fed Hartley guinea pigs [143]. Fucoxanthin is a carotenoid from edible brown algae that is characterized by its unique structure including an allenic bond and 5, 6-monoepoxide that differs from common carotenoids and has exhibited antiobesity and antidiabetic effects [144, 145]. Mice fed a fucoxanthinsupplemented HFD had reduced proinflammatory cytokine levels, including leptin, TNF-␣, monocyte chemotactic protein 1 (MCP-1), and IL-6, and increased adiponectin in plasma and adipose tissue [146, 147]. Fucoxanthin also decreased hepatic TG and cholesterol levels by suppressing activities of malic enzyme, FAS, glucose-6-phosphate dehydrogenase, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and acyl coenzyme A: cholesterol acyltransferase, thus decreasing hepatic lipogenesis and increasing ␤-oxidation [146]. Fucoxanthin reduces hyperglycemia and hyperinsulinemia both in HFD-fed C57BL/6N mice and diabetic/obese KK-A(y) mice [146, 147]. Fucoxanthin also decreased hepatic www.mnf-journal.com

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Brown algae

Fucoxanthin

DHA

Fish oils and golden algae oil

Spinach and kale

Lutein

EPA

Red palm oil, pumpkin, and leafy green vegetables

␤-Carotene

Omega-3 PUFAs

Tomatoes, watermelon, papaya and orange

Lycopene

Dietary source

Carotenoids

Structure

Compound

Class

Table 1. Chemopreventive activities and mechanisms of dietary natural compounds on NAFLD

r

r

r r

r r

r

r

-

r r r

r

r

SOD activity (Balb/c mice) Plasma adiponectin (C57BL6/N mice) Genes involved in lipolysis and ␤-oxidation (Kunming mice) Insulin sensitivity (C57BL6/N mice)

Plasma adiponectin (Balb/cA mice) CPT-1 (Medaka) AMPK␣ and PPAR␣ (Pten-deficient mice)

Plasma adiponectin (C57BL6/N mice)

Antioxidants (GSH, CAT, GR, and GST; SD rats, gerbils) Nrf2-dependent HO-1 (SD rats) Adiponectin (3T3-L1 cells) Glut4 (3T3-L1 cells) Antioxidants (CAT and GST; RD rats)

Upregulation

r

r

r

r

r

r r

r

r r

r

r

r

r

r r

r r

r

[146–148]

[143]

[140–142]

[136–139]

References

Inflammation and fibrosis (Ldlr(−/−), ob/ob mice) Hepatic lipogenesis (FAS and SREBP-1; ob/ob, Kunming mice) Kupffer cells activation (Ldlr (−/−) mice) IL-1␤ and TNF-␣ (Ldlr (−/−) mice)

[169–176]

Hepatocytes necrosis (Balb/cA [156–159, mice) 161–163] Inflammatory cells infiltration (Balb/cA mice) Oxidative stress (Balb/cA mice) SREBP-1 transcription factor (Medaka) Lipogenic and fibrogenic genes (HepG2 cells, Medaka, Wistar rats)

Proinflammatory adipokines (C57BL6/N mice, KK-A(y) mice) Hepatic lipogenesis (FAS, G6PD, and HMG-CoA reductase) (C57BL6/N mice) SCD-1 (KK-A(y) mice)

Lipid peroxidation (Guinea pigs) NF-␬B-mediated TNF-␣ (Guinea pigs)

Lipid peroxidation (RD rats) ROS production (3T3-L1 cells)

Hepatic inflammation (SD rats) Lipid peroxidation (SD rats) FABP7 (C57BL6/J mice)

Downregulation

Molecular mechanisms and targets

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Epigallocatechin3-gallate (EGCG)

Tea

r

r r

-

r

r

r

r

r

r

r

r

r r

r

PI3K/Akt signaling FA oxidation (UCP-2, SCD-1; New Zealand black mice) Dietary lipid oxidation (New Zealand black mice)

Antioxidants (SOD, CAT, and GPx) (C57BL/6, db/db mice) Nrf2-targeted genes (Wistar rats) ␻-oxidation (C57BL/6J mice) Glucose uptake (HepG2 cells)

FA oxidation (C57BL/6J mice) AMPK␣ and PPAR␣ (C57BL/6J mice)

Adiponectin secretion (ST-13 preadipocytes, 3T3-L1 cells) Insulin sensitivity (ob/ob, C57BL/6J mice)

CPT-1 (HepG2 cells) AMPK-dependent ACC phosphorylation (HepG2 cells)

AMPK signaling in adipocytes (3T3-L1 cells)

Upregulation

r

r r

r

r

r

r

r

r

r

r

r

r

Oxidative stress (SD rats) Hepatic inflammation, necrosis and fibrosis (TGF/SMAD signaling; SD rats) Plasma adipokines (C57BL/6 mice)

ROS production (Chang liver cells)

Proinflammatory cytokines (C57BL/6 mice, HepG2 cells) Lipogenic and fibrogenic genes (C57BL/6J, C57BL/6 mice) NF-␬B and JNK signaling (Wistar rats, C57BL/6 mice) Lipoperoxidation and DNA damage (C57BL/6 mice)

Hepatic inflammation (C57BL/6J mice) SREBP-1-dependent lipogenic genes (C57BL/6J mice)

Proinflammatory adipokines (ob/ob, C57BL/6J mice)

SREBP-1 and FAS (HepG2 cells)

HSL and lipolysis in adipocytes (3T3-L1 cells)

Downregulation

Molecular mechanisms and targets

[193]

[185–192]

[184]

[180–183]

[179]

[178]

References

M.-H. Pan et al.

Flavanols (catechins)

Broccoli and tea

Kaempferol

Baical Skullcap

Baicalein

Onion and broccoli

Citrus peels

Nobiletin

Quercetin

Parsley and celery

Luteolin

Flavonols

Parsley and celery

Apigenin

Dietary source

Flavones

Structure

Compound

Class

Table 1. Continued

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Isoflavones

Anthocyanidins

Flavanones

Class

Daidzein

Cyanidin-3-O-␤glucoside

Soybean

Cherries and strawberries

Citrus

Hesperetin

Black tea

Dietary source

Citrus

Structure

Naringenin

Theaflavin (TF-1)

Compound

Table 1. Continued

r

r

r

r

-

r

r

r

r

Antioxidants (SOD-2 and GST; Wistar rats)

GSH synthesis (HepG2 cells, db/db mice) AMPK signaling (HepG2 cells) FA oxidation (CPT-1) (HepG2 cells)

FA oxidation (CYP450 IVA1, PPAR␣, and PGC-1␣-targeted aCPT-1, ACO; ICR, Ldlr (−/−) mice) Insulin sensitivity (Ldlr (−/−) mice)

AMPK signaling (HepG2 cells) FA oxidation (HepG2 cells)

Upregulation

r

r

r

r

r

r

r

r

r

r

r

r

r r

r

r

r

De novo lipogenesis (C57BL/6J mice) SCD-1(Wistar rats, C57BL/6J mice)

TG synthesis (mtGPAT1; HepG2 cells, KK-A(y) mice) Neutrophil infiltration (db/db mice) Plasma adipokines (db/db mice) ROS production (HepG2 cells, db/db mice) JNK signaling (db/db mice) ACC activity (HepG2 cells)

PAP activity and TG synthesis (SD rats)

VLDL-TG and VLDL-apoB secretion (Ldlr (−/−) mice) Lipogenic genes (Ldlr (−/−) mice)

ACC activity (HepG2 cells) Oxidative stress and hepatocytes apoptosis (I/R injury mice) Inflammatory cytokines (I/R injury mice)

Inflammatory molecules (iNOS, COX-2, and TNF-␣; SD rats) FOXO1 and NF-␬B (SD rats) Dietary lipids incorporate to liver (C57BL/6 mice)

Downregulation

Molecular mechanisms and targets

[211, 212]

[207–210]

[205]

[202–204]

[200, 201]

[194–199]

References

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Other phenolic compounds

Class

Table 1. Continued

Turmeric

Curcumin

Dietary source

Grapes, red wine

Structure

Resveratrol

Genistein

Compound

r r

r

r

Mitochondria biogenesis and function (ob/ob mice, New Zealand rabbits, primary hepatocytes) Adiponectin of adipocytes (ob/ob mice) Insulin sensitivity (Akt signaling; HSCs) GCL activity (HSCs) AMPK signaling (HSCs)

FA oxidation (CPT-1 and ACO; Zucker, SD rats) Nrf2-targeted genes and antioxidants (SD rats) UCP-2 (Wistar rats) IRS-1/PI3K/Akt signaling and insulin sensitivity (C57BL/6J, KK-A(y) mice) SIRT1 activity and AMPK signaling (HepG2 cells, SD rats) FOXO deacetylation (HepG2 cells)

FA oxidation (PGC-1, PPAR␣ and CPT-1; HepG2 cells, C57BL/6J mice) Anti-oxidants (GPx, GR, and GSH; Wistar rats) IRS-1/PI3K/Akt signaling and Glut1 (HepG2 cells) Glucokinase activity (db/db mice)

Blood insulin and adipokines (C57BL/6J mice)

r

r

r

r

r

r

r

r

r

r

r

r

r

SREBP-1 and HMG-CoA reductase (ob/ob mice, SD rats) ROS production (New Zealand rabbits, primary hepatocytes, AML-12 hepatocytes) Inflammatory cells infiltration (NMRI mice) HSC activation and fibrogenic genes expression (HSCs)

Lipogenic genes (SREBP-1, FAS, ACC, G6PD, and HMG-CoA reductase; HepG2 cells, C57BL/6J mice, hamsters) Lipid peroxidation and oxidative stress (Wistar rats) Proinflammatory cytokines (Wistar rats) ER stress (HepG2 cells)

Hepatic inflammation and apoptosis (C57BL/6J mice) SREBP-1 and lipogenic genes (SD rats) Proinflammatory cytokines (C57BL/6J mice, SD rats) JNK and NF-␬B signaling (SD rats, HepG2 cells) PEPCK and G6Pase (db/db mice)

Downregulation

[242–255]

[226–229, 231–240]

[213–225]

References M.-H. Pan et al.

r

r

r

r r

r

r

r

r

r

r

r

Upregulation

Molecular mechanisms and targets

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157

[242–255]

r

r

Proinflammatory cytokines (ob/ob, NMRI mice, SD rats) JNK, NF-␬B, and SOCS3 (primary hepatocytes, ob/ob, NMRI mice) LDLR and LOX-1 (HSCs)

r

Downregulation Upregulation

FABP7, FA-binding protein 7; G6PD, glucose-6-phosphate dehydrogenase; GCL, glutamate-cysteine ligase GR, GSH reductase; ICR, institute for cancer research; iNOS, inducible nitric oxide synthase; RD, retinol deficiency.

Compound Class

Table 1. Continued

Structure

Dietary source

Molecular mechanisms and targets

References

Mol. Nutr. Food Res. 2014, 58, 147–171

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stearoyl-CoA desaturase 1 (SCD-1) expression, which is an enzyme that catalyzes MUFA biosynthesis from SFAs through leptin signaling regulation that suppresses 18:0 desaturation into 18:1n-9 in the liver [148].

3.2 Omega-3 PUFAs Growing evidence clearly demonstrates that an increased intake of marine omega-3 PUFAs, such as eicosapentaenoic acid (20:5 n-3, EPA) and docosahexaenoic acid (22:6 N-3, DHA), is beneficial to diverse physiological functions and human health, including the improvement of metabolic syndrome. Omega-3 PUFA supplementation has been shown to ameliorate hepatic steatosis in human studies and in different animal models [149–152]. Basically, the beneficial function of omega-3 PUFAs to NAFLD most likely is contributed by their incorporation into plasma phospholipids that modulate membrane fluidity and intracellular signaling or that alter the lipid composition of the liver [153]. In patients who have been diagnosed with a NASH, daily dietary intake of 2700 mg of EPA for 12 months resulted in decreasing the serum ALT, FFA, and thioredoxin levels, which contribute to hepatic oxidative stress. Among the 23 patients, seven of them showed improvement in hepatic steatosis and fibrosis. Decreased hepatocyte ballooning and lobular inflammation were found in six patients. The most safety concern of EPA is bleeding tendency, whereas there is no adverse event that has occurred during EPA treatment in all patients of this study [154]. A cross-sectional observational study showed the positive effect of dietary EPA in Japanese men with NAFLD but not in women that with unidentified reason [155]. In HFD-fed mice, dietary intake of EPA is effective in reducing fatty droplets by decreasing the hepatic cholesterol, TG, and nonesterified FAs [156, 157]. When mice were fed high sucrose/HFD supplemented with EPA, reduced D-galactosamine-induced hepatic injury occurred, as evidenced by a decreased hepatocyte necrosis and inflammatory cell infiltration. This result was also accompanied by lowered hepatic TG levels via the reduction of FAS and SCD-1 gene expression, decreased ROS production, and increased plasma adiponectin [158]. These effects could contribute to suppressing the progression of hepatitis. Moreover, EPA intake is found to abrogate HFD-induced SREBP-1, FAS, and ACC1 mRNAs, while increasing the CPT-1 expression; thus, it could decrease FA synthesis and promote mitochondrial ␤-oxidation [159]. A diet that is deficient in methyl groups, such as methionine and choline, is another animal model of NAFLD that is caused by impaired mitochondrial ␤oxidation [160]. Several studies have demonstrated that EPA decreased hepatic steatosis and the progression of fibrosis by suppressing TG synthesis and the expression of fibrogenic genes, such as TGF-␤1, ␣-smooth muscle actin (␣-SMA), and collagen [161, 162]. In Pten-deficient (liver-specific deletion of phosphatase and tensin homolog) mice, an NAFLD animal model characterized by increased hepatic lipogenesis, www.mnf-journal.com

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EPA improved steatohepatitis by reducing steatosis, lobular inflammation, and hepatocytes ballooning. Additionally, supplementation with dietary EPA for 76 wk reduced the amount of hepatocellular carcinoma. The suppressed effect of EPA is due to a decrease in hepatic ROS production and upregulation of AMP-activated protein kinase (AMPK) ␣ and PPAR␣ expression, which may repress the expression of lipogenic genes. Analyzing the lipid composition of the liver showed that EPA causes a dramatic change in the content of arachidonic acid and that EPA serves as the anti-inflammatory mechanism that acts as an inactive lipid mediator compared to arachidonic acid [163]. A recent study revealed that EPA and the oxidized form suppressed the liver X receptor agonistinduced TG synthesis in HepG2 cells by the downregulation of SREBP-1, a transcription factor that is involved in the expression of lipogenic genes, including FAS, ACC, and SCD1 [164]. Two controlled trial studies showed that children with NAFLD supplemented with 250 and 500 mg DHA per day for 6–24 months had improved liver steatosis and insulin sensitivity accompanied by lowered TG and ALT levels [165, 166]. Moreover, no adverse effect was found in 60 children with biopsy-proven NAFLD when supplemented with DHA supplementation at dosage of 250 and 500 mg for 6 months [161]. In animal models of diet-induced NAFLD, which included a high carbohydrate diet, HFD, and choline-deficient diet, the dietary intake of DHA reduced hepatic steatosis, inflammation, and fibrosis and decreased hepatic and serum total cholesterol levels and lipid peroxidation [167–169]. Increased SOD activity and decreased activity of SREBP-1 account for the inhibitory effect of DHA [167, 168]. Furthermore, alteration of the lipid and FA compositions and increases in omega-3 PUFAs in the liver provide a possible mechanism for the protective effect of DHA against NAFLD and NASH [169]. DHA was also found to ameliorate hepatic steatosis and inflammation by the downregulation of the expression of genes that are involved in TG synthesis (FAS, SREBP-1c, and PPAR␥). The suppression of Kupffer cells and macrophage activation, inflammatory cytokine production (IL-1␤ and TNF-␣), and nuclear NF-␬B accumulation occurred in dietary DHA-treated Ldlr−/− (deficient in the low-density lipoprotein [LDL] receptor) and leptin-deficient (ob/ob) mice [170, 171]. Mice treated with trans-10, cis-12conjugated linoleic acid developed NAFLD and insulin resistance, while supplementation with DHA reduced fatty liver, TG, and insulin levels and improved insulin resistance [172]. Compared to EPA, DHA is effective at restoring serum adiponectin levels, which contributes to improving hepatic insulin function [173]. An in vitro study showed that DHA decreased palmitate-induced lipid accumulation and inflammatory cytokine production through suppressing the activation of nucleotide-binding oligomerization domain (NOD) like receptor protein 3 inflammasomes, thus, in turn, blocking caspase-1-mediated IL-1␤ and IL-18 release [174]. There are a number of studies that have demonstrated that both EPA and DHA regulate a variety of genes that are im C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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plicated in lipogenesis, lipolysis, and ␤-oxidation in liver and adipose tissue, which suggests that they function on hepatic lipid metabolism and NAFLD [175, 176]. Although dietary intake of omega-3 PUFAs is exerting a beneficial effect on NAFLD, studies exhibited that increased hepatic lipid peroxidation also occurred. With regard to this finding, the addition of antioxidants is suggested for omega-3 PUFAs in the intervention of diseases [177].

3.3 Polyphenols Previous studies showed that many polyphenolic compounds in nature exert health-promoting effects when consumed in food.

3.3.1 Flavonoids Flavonoids are plant secondary metabolites that appear ubiquitously in fruits, vegetables, nuts, and seeds and can be classified into seven subgroups as follows: flavones, flavanones, flavonols, flavanonols, isoflavones, flavanols (catechins), and anthocyanidins, based on differences in the structure of the aglycone C ring. The diversity of the functional groups (by hydroxylation, methoxylation, or glycosylation) provides the structural variation and different biological properties of the flavonoids. More than 1000 natural flavonoids have been identified, and some of them exhibit a broad spectrum of biological properties and widespread beneficial effects for human health. 3.3.1.1 Flavones Apigenin (4 ,5,7-trihydroxyflavone) belongs to the flavone class and is most prevalent in parsley and celery. It has been reported that apigenin inhibited lipolysis of 3T3-L1 adipocytes by decreasing HSL gene expression and upregulating AMPK signaling, which can attenuate adipogenesis and FFA release from adipocytes [178]. Luteolin is another flavone and is most often present in thyme and other plants, including Brussels sprouts, cabbage, onion, broccoli, and cauliflower. Luteolin is also found to reduce palmitate-stimulated lipid accumulation in HepG2 cells by decreasing SREBP-1 and FAS as well as increasing CPT-1 gene expression. In addition, luteolin treatment induced AMPK signaling and, in turn, phosphorylated ACC (thus inhibiting the ACC activity) and reduced the production of malonyl-CoA, an allosteric inhibitor of CPT-1 that contributes to increased ␤-oxidation [179]. Nobiletin is a polymethoxyflavone that is rich in citrus peel and is reported to suppress proinflammatory adipokine production, such as the production of MCP-1 and TNF-␣, and to increase adiponectin secretion in adipocytes, both in vitro and in vivo [180–183]. In HFD-fed mice and leptin-deficient (ob/ob) mice, dietary intake of nobiletin improved plasma glucose tolerance and insulin sensitivity [181, 182], which suggests that insulin is acting on the improvement of adipose tissue-mediated www.mnf-journal.com

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insulin resistance, which plays a central role in the pathogenesis of NAFLD. Baicalein naturally occurs in the roots of Scutellaria baicalensis and has been found to reduce HFD-induced hepatic inflammation and lipid ectopic deposition by inhibiting SREBP-1-dependent lipogenic gene expression. Baicalein also enhances hepatic phosphorylated AMPK, PPAR␣, and its targeted gene expression and, thus, represses FA and cholesterol synthesis and promotes FA oxidation [184]. 3.3.1.2 Flavonols Quercetin is a natural flavonol that is typically present in onions, broccoli, and leafy green vegetables. Many in vivo studies have supported the preventive and therapeutic efficacy of quercetin against NAFLD. In HFD-fed animals, the dietary feeding of quercetin reduced hepatic lipid accumulation, the infiltration of inflammatory cells, and portal fibrosis, and it improved insulin resistance [185–187]. The mechanisms include the reduction of lipogenic gene expression, induction of ␻-oxidation, upregulation of Nrf2-targeted antioxidative enzyme expression, and a decrease in NF-␬B and serum IL-18 levels. Dietary quercetin also reduced hepatocellular fibrosis in HFD-fed gerbils through the regulation of Sirtuin (SIRT) 1, an NAD+ -dependent protein deacetylase that is known to impair the activity of PPAR␣, which results in a decrease in FA oxidation [188]. Feeding mice a methionineand choline-deficient diet supplemented with quercetin decreased liver steatosis and inflammatory cell accumulation through attenuating NF-␬B and JNK as well as reducing the fibrogenic gene expression, such as the expression of ␣-SMA, TGF-␤1, Col1␣1, and Col3␣1 [189]. The reduction of hepatic lipoperoxidation, DNA damage, and increased SOD, CAT, and GPx activities also contributes to the preventive action of quercetin against NAFLD [189,190]. In addition, quercetin has been shown to ameliorate hyperglycemia and to increase glucose uptake in diabetic db/db mice and oleic acid-treated HepG2 cells via increasing intracellular antioxidants and decreasing TNF-␣ and IL-8 expression [191, 192]. Kaempferol is another typical flavonol that is present in broccoli, tea, and various vegetables. Both kaempferol and quercetin prevented the production of peroxides, superoxide anion, and nitric oxide induced by proinflammatory cytokines in Chang Liver cells, which could reduce hepatic oxidative stress [193]. 3.3.1.3 Flavanols (catechins) Catechins and theaflavins (TFs) are bioactive compounds in green tea and black tea that have been shown to possess wide health benefits. Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenolic compound in green tea, and the dietary feeding of EGCG reduced HFD-induced hepatic steatosis, inflammation, and fibrosis, which can be attributed to decreased lipid peroxidation and ␣-SMA expression and increased GSH levels in liver [194,195]. EGCG prevented HFDinduced oxidative stress, and toxicity could be associated with reduced hepatic CYP2E1 that is overexpressed in NASH [194]. Long-term feeding of EGCG is effective in the reduction of  C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

159 HFD-induced hyperglycemia and plasma insulin levels and the improvement of insulin resistance, which could be the result of decreasing serum MCP-1, C-reactive protein, and IL-6 [195, 196]. Rats that received intraperitoneal injections of EGCG also reduced their HFD-induced hepatic fatty score, necrosis, inflammatory foci, and fibrosis, followed by decreasing TGF-␤1, ␣-SMA, TNF-␣, inducible nitric oxide synthase, and cyclooxygenase 2 gene expression through the modulation of the TGF/SMAD, PI3K/Akt/FOXO1, and NF-␬B signaling pathways [197]. Male New Zealand black mice that received orally administered EGCG decreased gene expressions of malic enzyme, SCD-1, and glucokinase in the liver, whereas uncoupling protein 2 (UCP-2) was increased, which could possibly be the cause of increased FA oxidation [198]. Another study used 13C-labeled palmitate and a diet that was supplemented with corn oil as a natural source of 13Cenriched lipids; this study showed that EGCG increased the oxidation of dietary lipids and decreased the incorporation of dietary lipids in the liver, thus reducing HFD-induced lipid accumulation in the liver [199]. TFs are major polyphenols in black tea that include theaflavin (TF-1), theaflavin-3-gallate, and theaflavin-3,3 -digallate. In human HepG2 cells, TF-1, theaflavin-3-gallate, and theaflavin-3,3 -digallate are more effective than (-)-epicatechin (EC), (-)-epicatechin gallate (ECG), (-)-epigallocatechin (EGC), and EGCG on reduction of mixture of long-chain FA-induced lipid accumulation. These theaflavins are potent at inducing the activation of AMPK and the inactivation of ACC, both in HepG2 cells and in the livers of HFD-fed mice [200]. By measuring the rates of incorporation of [14C]acetate into the hepatic FAs, theaflavins were found to reduce FA synthesis while increasing FA oxidation [200]. Dietary TF-1 reduced hepatic steatosis, oxidative stress, hepatocyte apoptosis, and macrophage infiltration in methionine- and choline-deficient diet-fed and ischemiareperfusion (I/R) injured mice. Reduced ROS production and decreased TNF-␣, IL-6, and inducible nitric oxide synthase expression could be the major mechanisms of TF-1 [201]. 3.3.1.4 Flavanones Citrus peels are a rich source of naringenin and hesperetin, both belong to the flavanones subgroup. An animal study showed that a normal diet supplemented with naringenin can increase gene and activity of various enzymes that are involved in hepatic FA oxidation, including carnitine octanoyltransferase, acyl-coenzyme A oxidase (ACO), bifunctional enzyme, and 3-ketoacyl-coenzyme A thiolase, as well as their gene expression, while they are not found in hesperetintreated mice. Naringenin also significantly increased the gene expression of microsomal CYP IV A1, which is involved in the ␻-oxidation of FAs [202]. Similar effects also occurred in HFD-fed Ldlr−/− mice. Dietary feeding of naringenin ameliorated hepatic steatosis, which is evidenced by a reduction in hepatic TG and VLDL–TG and VLDL–apolipoprotein B secretion. This effect resulted from naringenin increasing PPAR␣ and PPAR␥ peroxisome proliferator-activated receptor ␥ coactivator-1␣, which is mediated by CPT-1 and www.mnf-journal.com

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acyl-CoA oxidase gene expression (which are enzymes that are involved in mitochondrial and peroxisomal FA oxidation) [203]. In high cholesterol-fed mice, in addition to increased FA oxidation, naringenin also reduced hyperlipidemia and hepatic steatosis by the reduction of cholesterol and FA synthesis via downregulation of the expression of various genes in liver [204]. Moreover, improved glucose utilization and insulin sensitivity were found in naringenin-supplemented mice [203,204]. Another citrus flavanone, hesperetin, is found to decrease orotic acid induced hepatic TG accumulation and cholesterol levels, which contributes to reducing hepatic microsomal phosphatidate phosphohydrolaseactivity, which is the rate-limiting enzyme for TG synthesis [205]. 3.3.1.5 Anthocyanidins Anthocyanidins are plant pigments that have red and blue colors and that commonly occur in fruits and vegetables, such as blueberries and grapes. Several in vitro and in vivo studies revealed the function of cyanidin-3-O-␤-glucoside on insulin-resistance-associated NAFLD. Diabetic/obese KK-A(y) mice are an animal model of type 2 diabetes that exhibit a phenotype with severe obesity, hyperlipidemia, and insulin resistance [206]. Feeding cyanidin-3-O-␤-glucoside ameliorated hepatic steatosis by the reduction of TG synthesis via the downregulation of mitochondrial acyl-CoA:glycerolsn-3-phosphate acyltransferase 1, an enzyme that is involved in converting glycerol-3-phosphate and acyl-CoA into phosphatidic acid, which is a precursor of TG and glycerophospholipids [207]. In both HFD-fed and diabetic db/db mice, the oral administration of cyanidin-3-O-␤-glucoside reduced hepatic steatosis and neutrophil infiltration [208]. Cyanidin-3-O-␤-glucoside also attenuated obesity-associated insulin resistance by lowering the fasting glucose levels. Additionally, cyanidin-3-O-␤-glucoside decreased proinflammatory adipokine expression in adipose tissue and in plasma through the suppression of JNK signaling [208]. Another study showed the effect of cyanidin-3-O-␤-glucoside on the reduction of hepatic steatosis, neutrophil infiltration, and hepatocyte apoptosis through preventing oxidative injury that is evidenced by the inhibition of ROS production and the increase of GSH synthesis, both in high glucose-treated HepG2 cells and in diabetic db/db mice [209]. In addition to the antioxidative property, cyanidin-3-O-␤-glucoside increases cellular AMPK activity and suppresses ACC activity, thus causing decreased malonyl-CoA levels and further stimulation of CPT-1, which leads to enhanced FA ␤-oxidation and finally inhibits lipid accumulation in HepG2 cells [210]. 3.3.1.6 Isoflavones Isoflavones, such as genistein and daidzein, are abundant in soybeans; these isoflavones are a subclass of flavonoids. Isoflavones have been considered to be phytoestrogens and are recognized for improving health and aiding in the prevention of various diseases. In HFD-fed mice, daidzein reduced hepatic steatosis and de novo lipogenesis by downregulating  C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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gene expressions of ACC␤, FAS, adenosine triphosphate citrate lyase, and 1-acylglycerol-3-phosphate O-acyltransferase2 [211]. Daidzein also restored HFD-induced lowered SOD-2 and GST ␣3 gene levels. Another study also suggested that a reduction in PPAR␣ and SCD-1 could be an additional mechanism of daidzein-reduced hepatic steatosis [212]. Moreover, both studies showed that daidzein supplementation improved insulin resistance through decreasing blood insulin and adipokine (TNF-␣, leptin) levels. Genistein represents a potent chemopreventive agent that acts against NAFLD through the interaction of many different mechanisms that are related to lipid metabolism, energy metabolism, insulin sensitivity, and mitochondrial function. A study compared the activity of genistein and daidzein in the modulation of lipid metabolic gene expression in liver using microarray analysis. The result demonstrated that genistein was more effective than daidzein in lowering TG levels by targeting many genes that are involved in lipid and carbohydrate metabolism [213], although another in vitro study suggested that both genistein and daidzein upregulated CPT-1A enzyme activity [214]. Two in vitro studies also showed the ability of genistein to modulate gene expression that is involved in FA oxidation and to suppress lipogenesis via targeting the transcription factors PPAR␣ and SREBP-1 [215, 216]. Dietary intake of genistein decreased hepatic steatosis, inflammatory cells infiltration, and hepatocyte ballooning in HFD-fed rats and mice. These effects could contribute to genistein alternating between adipocyte metabolism and reduced TNF␣ production [217, 218]. Moreover, genistein decreased liver fat accumulation, possibly through increasing FA oxidation, as evidenced by increased PGC-1 and PPAR␣-target genes, peroxisomal acyl-CoA oxidase, and mitochondrial medium chain acyl-CoA dehydrogenase, as well as UCP-2 [219]. A study that used neonatal rats fed a diet with genistein showed decreased hepatic steatosis and inflammation by reducing FAS and SREBP-1 expression, but there was no effect on PEPCK and G6Pase. Hepatocyte apoptosis and hepatic TNF-␣ expression were also reduced [220]. Genistein treatment decreased HFD-induced hepatic inflammation with lowered levels of TNF-␣ and IL-6 in male sprague dawley (SD) rats. The results of molecular studies showed genistein suppression of JNK and NF-␬B inflammatory signaling, which suggests that anti-inflammation is one of the mechanisms that accounts for genistein impacting the prevention of NASH [221]. High glucose-treated rats supplemented with genistein had improved insulin resistance and liver injury through the increased activities of enzymatic (GPx, GSH reductase, and GSH) and nonenzymatic (vitamin C and E) antioxidants as well as by decreased 3-nitrotyrosine, a biomarker of inflammation that is formed by the reaction between ONOO− and the free tyrosine or tyrosine residues found in proteins [222]. Genistein also improved hepatic insulin signaling by the upregulation of IRS-1/PI3K-Akt signaling in high fructoseand HFD-fed mice [223]. Genistein supplementation elevated hepatic glucokinase activity, while suppressing the elevation of hepatic gluconeogenic G6Pase and PEPCK www.mnf-journal.com

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activities in diabetic db/db mice, which modulates hepatic glucose metabolism and contributes to improved insulin sensitivity [224]. In palmitate-treated HepG2 cells, genistein is found to improve glucose uptake by the upregulation of IRS1/PI3K signaling and Glut1 as well as by the inhibition of JNK signaling [225]. These studies suggested that genistein could act as an insulin sensitizer that contributes to improving insulin resistance mediated by NAFLD. 3.3.2 Resveratrol Resveratrol (3,5,4 -trihydroxystilbene), a compound found largely in the skins of red grapes, is widely accepted as a chemopreventive agent and exerts positive health effects by its multiple biological activities, such as antioxidative, antiinflammatory, anticancer, antiobesity, antidiabetic, and antiaging properties. The beneficial effect of resveratrol on metabolic syndrome has also been addressed. A number of in vivo animal models of NAFLD have exhibited the potential inhibitory effect of resveratrol. In several models of HFDinduced NAFLD, dietary intake of resveratrol efficiently suppressed hepatic steatosis; reduced lipid, cholesterol, and TG accumulation; inhibited inflammatory cell infiltration; and inhibited insulin resistance. The molecular mechanisms include decreased lipogenesis, as shown by reduced gene expression levels of SREBP-1, FAS, ACC, glucose-6-phosphate dehydrogenase, and HMG-CoA reductase, and increased FA oxidation by the upregulation of CPT-1 and ACO [226–230]. However, two studies showed that a dose–response effect was not found in resveratrol treatment [229, 231]. Male C57BL/6J mice fed 0.005% or 0.02% resveratrol reduced HFD-induced hepatic steatosis, whereas the lower dose of resveratrol (0.005%) appeared to be more beneficial than the higher dose (0.02%). Another study showed that male fa/fa Zucker rats, an animal model of obesity and liver steatosis, orally administered resveratrol at 15 and 45 mg/kg body weight reduced liver weight, TG content, and oxidative stress. This inhibitory effect of resveratrol contributes to increase enzyme activity of CPT-1 and ACO. Nevertheless, a dose–response pattern was not found of resveratrol treatment in this study. By using microarray analysis, dietary resveratrol is found to modulate the expression of various genes that are involved in hepatic lipid metabolism, including cholesterol, FA, and lipid synthesis and metabolism as well as transport [232]. Resveratrol has been shown to possess potent antioxidative activity that prevents hepatic steatosis by decreasing oxidative stress and upregulating antioxidative enzymes. Resveratrol upregulated hepatic UCP-2, an anion transporter that is located in the inner mitochondrial membrane that functions to reduce the electrochemical gradient over the membrane, and it increased the mitochondria content; thus, it could protect against HFDinduced mitochondrial dysfunction in hepatocytes [233]. The oral consumption of resveratrol is shown to suppress lipid peroxidation by the upregulation of Nrf2 and by antioxidants, including catalase, SOD, GSH, and vitamin C, which reduced fructose-induced hepatic oxidative stress [234]. Lowered hep C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

atic TNF-␣ has also occurred in resveratrol-treated rats, which suggests that there is an anti-inflammatory function of resveratrol in HFD-induced NAFLD [235]. Resveratrol attenuated insulin resistance and reduced blood glucose, serum insulin, and the hepatic glycogen content in HFD-fed mice and diabetic/obese KK-A(y) mice, which is attributed to the upregulation of IRS/PI3K/Akt signaling in the liver and improved insulin sensitivity [236, 237]. Moreover, resveratrol is known to induce SIRT1, a member of the mammalian SIRTs, which are highly conserved protein deacetylases, and AMPK signaling that might contribute to the modulation of many transcription factors and molecules that are involved in lipogenesis and insulin signaling. In palmitate-treated HepG2 cells, treatment by resveratrol-induced SIRT1 and FOXO further downregulated SREBP-1 expression and reduced lipid accumulation [238]. When HepG2 cells were exposed to high glucose, resveratrol abrogated the impairment of the phosphorylation of AMPK and its downstream target, ACC, as well as counteracted increased expression of FAS and lipid accumulation. In addition, the activation of AMPK signaling is correlated with resveratrol-stimulated SIRT1 activity [239]. A new study showed that resveratrol ameliorated palmitate-induced deregulation of insulin signaling and ER stress through the activation of SIRT1-dependent FOXO deacetylation [240]. 3.3.3 Curcumin Curcumin (diferuloylmethane) is the major pigment from dried rhizomes of the turmeric plant (Curcuma longa Linn) and has been used as a spice and traditional medicine in Asia for centuries. The chemopreventive property of curcumin against various diseases and cancers has been confirmed in a number of studies. Many previous in vivo studies have also demonstrated the protective and therapeutic potential of curcumin on NASH and NAFLD using different animal models [241]. The mechanisms included anti-inflammatory and antioxidative properties, inhibition of HSC activation, reduced lipogenesis, and improved insulin sensitivity. Dietary curcumin decreased hepatic TG levels by the downregulation of SREBP-1 and HMG-CoA reductase gene expression and by increased mitochondrial biogenesis in HFD-fed obese mice [242, 243]. Curcumin also suppressed macrophage infiltration in liver tissue with lowered NF-␬B, SOCS3, MCP1, and TNF-␣ in HFD-fed mice and leptin-deficient (ob/ob) mice [242–244]. In HFD-fed New Zealand rabbits, a diet supplemented with curcumin reduced hepatic steatosis, inflammation, and fibrosis, which is attributed to lower mitochondrial ROS and improved mitochondrial function [245]. Improved insulin and glucose tolerance occurs from curcumin treatment in HFD-fed C57BL/6J mice, leptin-deficient (ob/ob) mice, and cultivated human adipose tissues, and could contribute to the lowered adipose tissue-derived proinflammatory adipokines and increased adiponectin [244, 246]. TNF-␣ is known to trigger the recruitment of inflammatory cells and is a pathogenic factor in NAFLD. In mice administered TNF-␣ intraperitoneally, curcumin repressed the infiltration www.mnf-journal.com

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Figure 1. Pathogenesis and development of NAFLD/NASH. Increased FFAs overflow from adipose tissue or diet activates JNK and NF-␬B signaling where induces transcriptional expression of proinflammatory cytokines (such as TNF-␣) and further cause IR. Adipokines derived from adipose tissue also cause hepatic insulin receptor (IR) via JNK and SOCS3 mediates IRS-1 serine phosphorylation, results in decreasing glucose uptake and promoting gluconeogenesis. FFAs trigger de novo lipogenesis through SREBP-1 transcription factor mediated lipogenic genes resulting TG accumulation. Upregulated PPAR␣ by FFAs induce CPT-1 expression that facilitates FFAs import to mitochondria. PPAR␣ also increases enzymes involved in peroxisomal and mitochondrial oxidation. Increased ROS from FAs oxidation and CYP2E1 results in lipid peroxidation and oxidative stress contributes to mitochondria dysfunction and hepatocytes injury. FFAs activated JNK, TNF-␣, and oxidative stress are contributed to hepatocytes lipotoxicity and apoptosis, further induce recruitment of inflammatory cells that enhance release of cytokines and activation of HSCs. Transactivated HSCs produce fibrogenic molecules that facilitate NASH development.

of Kupffer cells and neutrophils in the liver and further reduced myeloperoxidase activity, lipid peroxidation, and nitrite content [247]. In vitro studies exhibited that curcumin treatment restored mitochondrial dysfunction and suppressed ROS production and PEPCK and G6Pase production as well as activating Akt signaling, which occurs via blocking the JNK signaling. These effects might further improve insulin sensitivity in FFA and iron overload mediated insulin resistance hepatocytes [248, 249]. Many studies suggested that the suppression of HSC activation by curcumin could be an important mechanism in preventing NASH progression. The activation of HSC occurs in response to hepatic injury and is involved in the development of hepatic fibrosis. When hepatic injury occurs, quiescent HSCs undergo enhanced cell proliferation, the loss of lipid droplets, expression of ␣-SMA, and excessive production of extracellular matrix. Treatment with curcumin inhibited insulin-stimulated HSC activation by increased intracellular lipid droplets and the expression of fibrogenic genes. Molecular studies demonstrated that curcumin interrupts insulin signaling and suppresses gene expression of the insulin receptor in HSCs. Moreover, curcumin eliminated insulin-induced ROS production and increased the activity of glutamate-cysteine ligase in activated HSCs, which indicates that ROS is implicated in insulin-mediated HSC ac C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

tivation [250]. In high glucose- and leptin-treated HSCs, curcumin suppressed HSC activation by abrogated membrane translocation of Glut proteins. These two studies showed that curcumin interfered with hyperleptinemia-triggered p38 mitogen-activated protein kinase and IRS/PI3K/Akt signaling, which lead to inhibiting HSC activation [251, 252]. Additionally, curcumin stimulated glucokinase activity, increasing the conversion of glucose to glucose-6-phosphate in HSCs [252]. Further study revealed that curcumin abrogated leptin-induced HSC activation contributes to the upregulation of AMPK and the induction of gene expression of PPAR␥, SREBP-1, and CCAAT/enhancer binding protein ␣, which leads to the accumulation of lipids [253]. Hypercholesterolemia is characterized by elevated levels of plasma LDL and is associated with NAFLD. Cellular uptake of oxidized LDL is mediated by binding to cell-surface LDL receptors of different cell types in the liver, which subsequently leads to cholesterol uptake and increased ROS. Curcumin treatment is found to suppress LDL and oxidized LDL induced activation of HSCs, especially through downregulated LDL receptor and lectin-like oxidized LDL receptor 1 expression, which results in decreased fibrogenic gene expression and intracellular cholesterol [254, 255]. Although curcumin is known to have various biological properties, poor absorption www.mnf-journal.com

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and systemic bioavailability have been considered as a major limitation for its application in clinic [256].

4

Conclusion

NAFLD pathogenesis is a complicated process that is involved not only in molecular changes within the liver, but also in metabolic signaling between organs. Understanding the pathogenic factors, signaling networks, and molecular mechanisms that are implicated in NAFLD could provide biomarkers for treatment and intervention. Considerable accomplishments in NAFLD research over the past few decades have verified that increased oxidative stress, lipotoxicity, insulin resistance, ER stress, hepatic inflammation, and obesity play causal roles in the development and progression of this disease and also offer opportunities for using nutritional components as prevention or intervention. Furthermore, dietary natural compounds provide a novel strategy for obesity-associated NAFLD treatment. These dietary natural compounds have great potential to not only influence development and NAFLD progression, but also to target obesity and insulin resistance-mediated pathogenesis. This general beneficial effect of dietary natural compounds demonstrates a complex interaction of many different mechanisms, including a reduction in lipogenesis, an increase in FA oxidation, an improvement in insulin signaling, an inhibition of adipokine production, an elimination of oxidative stress, and the suppression of hepatic inflammation by targeting multiple signaling pathways, transcription factors, and enzymes. The coordination of metabolic function between liver and adipose tissue by dietary natural compounds also represents a potential mechanism to prevent hepatic steatosis, inflammation, and fibrosis (Fig. 1). Although the current knowledge suggests that dietary natural compounds could be helpful for NAFLD prevention and treatment, most of these dietary natural compounds are lack of understanding about relevance to human, such as the dosage, bioavailability, and possible adverse effects. Well-designed experiments, appropriately powered and large-scale trials are needed to examine the applicability and roles of these dietary natural compounds as chemopreventive agents of NAFLD. This study was supported by the National Science Council NSC 101–2628-B-022–001-MY4, 102-2628-B-002-053-MY3. The authors have declared no conflict of interest.

5

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