Molecular mechanisms of fatty liver in obesity

Abstract

Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver disorders ranging from simple steatosis to advanced pathologies, including nonalcoholic steatohepatitis and cirrhosis. NAFLD significantly contributes to morbidity and mortality in developed societies. Insulin resistance associated with central obesity is the major cause of hepatic steatosis, which is characterized by excessive accumulation of triglyceride-rich lipid droplets in the liver. Accumulating evidence supports that dysregulation of adipose lipolysis and liver de novo lipogenesis (DNL) plays a key role in driving hepatic steatosis. In this work, we reviewed the molecular mechanisms responsible for enhanced adipose lipolysis and increased hepatic DNL that lead to hepatic lipid accumulation in the context of obesity. Delineation of these mechanisms holds promise for developing novel avenues against NAFLD.

Keywords

nonalcoholic fatty liver disease / insulin resistance / obesity

Introduction

The prevalence of fatty liver disease is estimated to be 5%-18% in Asia and 20%-30% in Western societies [1-7]. An early and simple form of fatty liver disease is hepatic steatosis, which is characterized by accumulation of triglyceride (TG)-rich lipid droplets (LDs) within hepatocytes, but without hepatic inflammation or evidence of liver injury. Steatosis is diagnosed if hepatic TG content exceeds the 95th percentile for healthy individuals (i.e.,>55 mg per g of liver) or when cytoplasmic LDs exist in more than 5% of hepatocytes [8,9]. The etiology of hepatic steatosis is multifactorial and involves genetic determinants [10] as well as lifestyle or environmental factors, such as overnutrition, alcohol consumption, virus infection, drugs, or altered immune function. Nonalcoholic fatty liver disease (NAFLD) is the most common fatty liver disease. NAFLD covers a full spectrum of liver pathologies, including hepatic steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis. Simple hepatic steatosis is relatively benign; however, a small proportion of subjects with steatosis develop NASH, which may progress to hepatic fibrosis, cirrhosis, or cancer [11]. The absolute number of patients with these advanced liver abnormalities is estimated to be large because obesity is the most predominant cause of NAFLD [1-7], and obesity has been increasing alarmingly worldwide. In this work, we reviewed the molecular mechanisms of NAFLD, with focus on hepatic steatosis associated with obesity.

Hepatic TG metabolism in obesity-associated NAFLD

The liver plays a central role in lipid metabolism. Hepatic steatosis arises from an imbalance between TG formation and utilization. The free fatty acids (FFAs) used for hepatic TG formation are derived from three sources (Fig. 1): (1) diet, (2) de novo lipogenesis (DNL), and (3) adipose tissue lipolysis. About 60% of hepatic TG accumulated in the livers of NAFLD patients is derived from FFAs mobilized from peripheral adipose depots, 25% from DNL, and the remaining 15% from dietary lipids [12], which indicates that dysregulation of adipose lipolysis and hepatic DNL plays major roles in the pathogenesis of NAFLD. DNL normally occurs in the postprandial state and is stimulated by elevated blood glucose and insulin; lipolysis occurs in the fasting state; is induced by catecholamines, natriuretic peptides, and glucagon; and suppressed by insulin [13]. Therefore, disturbance of the endocrine system also directly contributes to the development and progression of NAFLD.

Increased hepatic fatty acid uptake

After eating, dietary lipids are packaged into chylomicrons as TGs and cholesterol esters and transported into the blood circulation. Chylomicron-TGs are then hydrolyzed by lipoprotein lipase localized at the luminal surface of tissue capillaries, releasing FFAs to adipose tissue for storage and other tissue for oxidation. Approximately 20% of chylomicron-derived FFAs are delivered to the liver [14]. In the fasting state, a decline of insulin level stimulates adipocyte TG hydrolysis to mobilize FFAs for use by nonadipose tissue, including the liver. However, in the insulin-resistant state, which is a condition often associated with central obesity, adipocyte lipolysis increases regardless of nutritional fluctuations, leading to the release of abundant FFAs into the blood [12]. In the liver, several membrane-bound proteins are responsible for transporting circulating FFAs into hepatocytes, including fatty acid transporter protein (FATP)-2 [15], FATP-5 [16], fatty acid translocase (FAT/CD36) [17-19], caveolins [20,21], fatty acid binding proteins (FABP)-1, FABP-4, and FABP-5 [22,23]. Upregulation of several FFA transporters is associated with increased insulin resistance and hepatic steatosis in NAFLD patients [24-27]. The expression levels of many FFA transporters are regulated by insulin and nuclear receptors, such as liver X receptor (LXR) [28,29], farnesoid X receptor (FXR) [30], pregnane X receptor (PXR) [31], peroxisome proliferator-activated receptor (PPAR)-α, and PPAR-γ [32] (see Table 1 for the functions and alterations of these nuclear receptors and other regulators in hepatic steatosis). Therefore, targeting these nuclear receptors is an attractive approach for NAFLD prevention.

Enhanced hepatic de novo lipogenesis

Although increased circulating levels of FFAs play a predominant role in driving hepatic steatosis in obesity, locally synthesized FFAs from glucose (DNL) also contribute a significant proportion (about one-third) of the total TGs deposited in the livers of NAFLD patients [12] (Fig. 1). In healthy subjects, DNL postprandially increases, which is mainly mediated by two transcriptional factors: sterol regulatory element binding protein-1c (SREBP-1c) [33], which is activated by insulin; and carbohydrate response element binding protein (ChREBP), which is activated by glucose [34,35]. SREBP-1c activation by insulin during carbohydrate feeding involves two mechanisms: transcriptional upregulation and proteolytic cleavage activation of SREBP-1c precursor [36-38]. SREBP-1c precursor resides at the endoplasmic reticulum (ER) membrane where it interacts with SREBP cleavage-activating protein (SCAP) [39,40]. SCAP interacts with insulin-induced gene (INSIG) protein, which retains the SREBP-1c/SCAP complex in the ER when cellular cholesterol is high [41]. After cholesterol depletion or in the presence of insulin, SCAP dissociates from INSIG, and the SREBP-1c/SCAP complex is transported to the Golgi apparatus by coat protein II vesicles [42,43]. In the Golgi apparatus, SREBP-1c precursor is sequentially cleaved by two proteases, namely, S1P and S2P, releasing its N terminus as the mature active form of the transcription factor to enter the nucleus and turn on lipogenic gene expression [44]. Paradoxically, in the insulin-resistant liver, lipogenesis is selectively enhanced despite resistance to insulin-mediated suppression of gluconeogenesis [45]. Emerging evidence suggests that ER stress activates the cleavage of insulin-independent SREBP-1c [46,47]. Inhibition of ER stress in obese rodents decreases SREBP-1c activation and lipogenesis and improves hepatic steatosis and insulin sensitivity [48]. This observation may explain the paradoxical stimulation of lipogenesis in insulin-resistant liver.

ChREBP localizes in the cytoplasm when cellular glucose is low and enters into the nucleus when cellular glucose is high [35]. Glucose activates ChREBP [35,49] by stimulating its expression, regulating its translocation from the cytoplasm to the nucleus, and promoting its binding to carbohydrate responsive element (ChoRE). ChoRE is present in the promoters of glycolytic and lipogenic genes, such as acetyl-CoA carboxylase 1, fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD-1) [35,50,51]. ChREBP-mediated activation of lipogenic genes may increase TG synthesis. Consistently, NAFLD patients display increased hepatic enzyme activities for TG synthesis, including glycerol-3-phosphate acyltransferase, 1-acylglycerol-3-phosphate acyltransferase, and diacylglycerol acyltransferase [52-54]. In NAFLD patients, DNL is augmented under fasting condition and does not further increase postprandially, suggesting that the liver of these individuals may have reached its maximal capacity in DNL [12,55].

Altered hepatic TG secretion

Hepatic TGs can be packaged as a constituent of very low density lipoprotein (VLDL) for secretion into the blood circulation. The assembly of VLDL particles occurs in the ER and involves interactions between lipids and apolipoprotein (apo) B100 (apoB100) [56]. This process is facilitated by microsomal TG transfer protein (MTP), an ER resident protein that has both apoB100 binding and lipid transfer activities [57]. The rate of VLDL secretion depends not only on the availability of hepatic lipids, particularly TGs, but also on the overall capacity of hepatocytes for VLDL assembly. When TGs are unavailable, lipid-free apoB100 is degraded via proteasomal and nonproteasomal pathways [58]. Insulin plays an important role in regulating the capacity of VLDL assembly. In response to insulin action, apoB100 is degraded [58], and MTP expression is suppressed [59]. Impaired VLDL assembly and secretion may cause excessive lipid accumulation in the liver, as seen in patients with hypobetalipoproteinemia because of apoB mutation [60] or abetalipoproteinemia because of MTP mutations [61]. However, NAFLD is characterized by increased expression of hepatic apoB100 and MTP [62,63]. NAFLD is also characterized by overproduction of VLDL particles, which may reflect enhanced lipid availability from fat lipolysis and hepatic DNL, and the failure of insulin to suppress VLDL production. Augmented VLDL secretion may be a compensatory mechanism to protect the liver from steatosis under overnutritional conditions. However, under the condition of prolonged overnutrition, this mechanism may fail to counter-balance chronic increases in liver TG synthesis, thereby resulting in hepatic steatosis.

Roles of hepatic TG hydrolysis and fatty acid oxidation in NAFLD

Another metabolic pathway for the disposal of hepatic TGs is fatty acid β-oxidation, which mainly occurs in the mitochondria. Excessive TGs are stored in cytosolic LDs, and these stored TGs have to be mobilized via hydrolytic process to release FFAs for utilization. TG hydrolysis requires functional hydrolases. The deletion of adipose triglyceride lipase (ATGL) directly induces hepatic steatosis [64]. The full activation of ATGL requires a coactivator named comparative gene identification-58 (CGI-58) (also known as α/β-hydrolase domain-containing 5 or Abhd5) [65]. Although CGI-58 may function via activating ATGL, liver-specific deletion of CGI-58 relative to ATGL in mice causes a more advanced NAFLD, including NASH and hepatic fibrosis [66]. Liver-specific ATGL knockout mice develop simple steatosis but not NASH and fibrosis [64]. Therefore, CGI-58 plays a vital role in the development and progression of NAFLD. Future studies are required to delineate the underlying molecular mechanisms.

Human genetic studies have identified certain genetic variations in human patatin-like phospholipase domain containing protein 3 (PNPLA3) gene that predispose susceptibility to NAFLD and disease severity [67,68]. PNPLA3 is a homolog of ATGL (also known as PNPLA2). Interestingly, these PNPLA3 mutants are sequestered to the cytosolic LDs where they may interfere with LD homeostasis [69]. Collectively, animal and human studies support a critical role of intracellular LD homeostasis in regulating hepatic fat content.

FFAs released from cytosolic LDs may enter the mitochondria for oxidation. This oxidative process progressively shortens FFAs to generate two carbon acetyl-CoAs. Acetyl-CoAs either condense into ketone bodies as energy substrates for extrahepatic tissue or enter the tricarboxylic acid cycle for ATP production. Other oxidative pathways of FFAs include peroxisomal-β-oxidation and microsomal-ω-oxidation. In general, short- (<C8), medium- (C8-C12), and long-chain (C12-C20) fatty acids are oxidized within the mitochondria, whereas very-long-chain (>C20) fatty acids are oxidized within peroxisomes. In diabetes or during FFA overload, cytochrome P450-dependent ω-oxidation of long-chain fatty acids occurs in the ER, which induces reactive oxygen species production and lipid peroxidation [70]. In the fed state, FFA oxidation is inhibited while DNL is activated, allowing storage and distribution of lipids. This phenomenon occurs because malonyl-CoA generated in the lipogenic pathway is a potent allosteric inhibitor of carnitine palmitoyl transferase I [71], a rate-limiting enzyme in transporting acyl-CoA from cytosol into the mitochondria. During fasting or caloric restriction, members of the sirtuin (SIRT) gene family, especially SIRT1 and SIRT3 [72,73], are increased to promote fatty acid oxidation by activating PPAR-α [74], PPAR-γ coactivator 1α [75], and their target genes that are mainly involved in mitochondrial and peroxisomal fatty acid oxidation. Hepatocyte-specific deletion of SIRT1 impairs PPAR-α signaling and decreases fatty acid β-oxidation, resulting in hepatic steatosis [76,77], whereas SIRT1 overexpression attenuates hepatic steatosis and ameliorates systemic insulin resistance in obese mice [78]. SIRT1 also reduces hepatic lipogenesis by inhibiting SREBP-1c [79], increases energy expenditure by inducing fibroblast growth factor (FGF) 21 [80], and promotes lipolysis in adipocytes via FOXO1-mediated increase in ATGL expression [81]. Degradation of SIRT1 protein contributes to hepatic steatosis in obese mice [82]. FGF21 is a hepatocyte-derived hormone that exhibits many beneficial effects on lipid and energy metabolism, such as increasing fat utilization and lipid excretion, inhibiting hepatic steatosis, stimulating energy expenditure, and reducing body weight [83-87]. FGF21 is an atypical member of the FGF family that shows no undesirable tumor-promoting effects and therefore has a potential for therapeutic use in diabetes and obesity-related metabolic disorders.

PPARs are nuclear receptors critically implicated in both fatty acid oxidation and lipid synthesis. The PPAR family has three members, namely, PPAR-α (NR1C1), PPAR-γ (NR1C3), and PPAR-δ (NP1C2) [88]. Each PPAR is encoded by a different gene and activates its target genes after binding to the PPAR-response elements of target genes as a heterodimer with retinoid X receptor<FootNote>

See comment in PubMed Commons below

</FootNote>. PPAR-α is predominantly expressed in tissue capable of oxidizing fatty acids, such as liver, heart, muscle, brown adipose tissue, and kidney. FFAs are believed to be the endogenous ligands for PPARs. Synthetic PPAR-α ligands, such as fibrates, have been approved for clinical use in subjects with hypertriglyceridemia. PPAR-α activation results in increased fatty acid uptake and oxidation through mitochondrial- and peroxisomal-β oxidation. Similar with PPAR-α, PPAR-δ is also a potent metabolic regulator with actions on fat, macrophage, skeletal muscle, liver, and heart. PPAR-δ activation enhances fatty acid transport and oxidation, improves glucose homeostasis, reduces macrophage inflammatory responses, and increases circulating high-density lipoprotein levels [89]. PPAR-γ is a master regulator of adipogenesis, thereby playing an important role in lipid storage. PPAR-γ is most highly expressed in adipocytes, macrophages, muscle, and to a less degree in hepatocytes. Activation of PPAR-γ by the agonist thiazolidinediones has multiple benefits, including improving insulin resistance, reducing circulating levels of FFAs and aminotransferases, and suppressing hepatic inflammation and fibrosis [90,91]. Improved insulin sensitivity is expected to reduce lipid deposition in the liver.

Interestingly, rodent and human studies suggest that lipid disposal through β-oxidation or export has limited effect on TG accumulation in NAFLD [92]. The DNA-binding activity and expression levels of PPAR-α in human hepatocytes are 10-fold less than those observed in mice; several PPAR target genes, such as acyl-CoA oxidase, which is the rate-limiting enzyme in peroxisomal fatty acid β-oxidation, do not respond to PPAR ligands in humans as they do in rodent models [93]. Additionally, alterations in rates of hepatic fatty acid oxidation in humans with NAFLD are not conclusive, and both increased and decreased fatty acid oxidation have been reported [94,95]. In agreement, a clinical study showed that two common pharmacological drugs used to treat hypertriglyceridemia (i.e., fibrate and nicotic acid derivatives that target fatty acid oxidation and hepatic VLDL secretion) exert no effects on hepatic TG content in obesity-associated NAFLD [96].

miRNAs and fatty liver

Recently, a class of small noncoding microRNAs (miRNAs or miRs) has emerged as crucial regulators of hepatic lipid homeostasis [97]. miR-122 consists of ~70% of the total miRNAs in the liver and is a completely conserved liver-specific miRNA in vertebrates [98,99]. miR-122 increases the hepatic expression levels of several lipogenic genes, such as FAS, ACC, and SCD-1 [100,101]. Patients with simple steatosis or NASH display significantly elevated serum levels of miR-122 [102]. The hepatic expression of miR-122 is reduced in NASH compared with simple steatosis in humans [102,103]. Decreased hepatic levels of miR-122 have been proposed to contribute to liver inflammation during NAFLD progression. In agreement, liver-specific deletion of miR-122 causes NASH, hepatic fibrosis, and hepatocellular carcinoma [104,105].

Other miRNAs, such as miR-33 [106], miR-34 [107], miR-370 [108], and miR-613 [109], also affect hepatic expression levels of genes related to DNL regulation or fatty acid oxidation. Emerging evidence suggests that dysregulation of these miRNAs is associated with liver inflammation, cirrhosis, and cancer [96]. The miRNAs known to participate in multiple aspects of hepatic TG metabolism and their alterations in obesity-associated NAFLD are summarized in Table 1.

Autophagy and fatty liver

Autophagy is a catabolic process that targets the constituents of a cell, such as damaged organelles and LDs to lysosomes, for degradation. Under physiological conditions, autophagy participates in the basal turnover of lipids and other cellular components. In response to environmental cues such as prolonged starvation, autophagic turnover increases to maintain cellular energy homeostasis. A recent study has demonstrated that downregulation of lipophagy, a lipid-specific macroautophagy, promotes steatosis in the liver of genetic and dietary obese mice [110]. In addition, hepatic autophagy is decreased in obese mice [111]. Several mechanisms may account for this decline in autophagy [112]: (1) increased degradation of autophagy-related gene-7 by an obesity-induced calcium-dependent protease calpain-2 [111]; (2) hyperactivation of the mammalian/mechanistic target of rapamycin signaling, a major autophagy inhibitory pathway, by increased amino acid flux into hepatocytes following overnutrition [113]; and (3) a defect in lysosomal acidification and reduction in cathepsin L that impairs substrate degradation in autolysosomes [114]. Cathepsin B, D, and L expression levels are significantly decreased in the liver of NAFLD patients [115]. Obesity-associated alterations in other signaling pathways may also regulate autophagy to influence NAFLD development and progression, particularly pathways involved in energy sensing of cells, such as AMPK and PI3K.

Adipose dysfunction and hepatic steatosis

Even though the causes for NAFLD may include drugs, genetic disorders, parenteral nutritions, etc., the vast majority of NAFLD cases are seen in the obese population [1-7]. The strong positive association between obese adipose tissue and NAFLD is supported by several lines of evidence: (1) epidemiological data show that the prevalence of hepatic steatosis is 70%-90% in obese adults, which is much higher than 20%-30% in general population [1-7]; (2) quantitative metabolic studies in humans reveal that about 60% of hepatic lipids in NAFLD patients originated from adipose-derived FFAs [12]; and (3) weight-loss bariatric surgeries are, so far, the most efficient way in reducing hepatic TG content in obese subjects [116]. In addition, diet-induced weight loss or increased physical activity also reduces hepatic TG [117]. The fact that patients with lipodystrophy exhibit severe hepatic steatosis [53] supports the important role of adipose tissue in regulating the pathogenesis of NAFLD.

Adipose tissue lipolysis

Recent years have witnessed tremendous progresses in identifying enzymes and factors that regulate fat lipolysis [118]. We now know that adipose lipolysis is mediated by three distinct lipases, namely ATGL [119], hormone sensitive lipase (HSL) [120] and monoacylglycerol lipase (MGL) [121]. Under basal lipolytic conditions, hydrophobic TGs in LDs are surrounded by a phospholipid monolayer and unphosphorylated perilipin 1 (PLIN1), a LD coat protein [122]. PLIN1 interacts with CGI-58 in adipocytes [123,124]. Unphosphorylated PLIN1 was hypothesized to prevent ATGL activation by sequestering its co-activator, CGI-58 [125,126]. Upon stimulation of lipolysis, PLIN1 phosphorylation causes dissociation of CGI-58 with PLIN1, allowing CGI-58 to bind and activate ATGL [126]. ATGL activation is negatively regulated by G₀/G₁ switch gene 2 protein [127,128]. In addition, lipolysis is influenced by intracellular proteins controlling the size of LDs, such as members of the cell-death inducing DNA fragmentation factor-α-like effector family [129-131]. Major positive regulators of human lipolysis include catecholamines and natriuretic peptides, whereas the major antilipolytic factor is insulin.

Under physiological conditions, adipose lipolysis is regulated by fasting/fed states. In the fasting state, FFA mobilization is stimulated because of reduced insulin and increased adrenaline and noradrenaline in the blood. On the surface of adipocyte, the binding of adrenaline and noradrenaline to their specific β-adrenergic receptors (G-protein-coupled receptors) causes G-proteins to interact with adenylyl cyclase, generating cAMP from ATP substrate. cAMP subsequently activates protein kinase A (PKA), leading to PLIN1 phosphorylation and initiation of a lipolytic cascade [13,126,132,133]. In addition, PKA-mediated phosphorylation of HSL causes the rapid activation and translocation of HSL from the cytosol to the surface of LDs where HSL interacts with the phoshorylated PLIN1 and gains access to diacylglycerol substrate generated by ATGL [132,133]. After eating, increased plasma insulin suppresses lipolysis to promote storage of dietary lipids. Binding of insulin to its receptor induces autophosphorylation of insulin receptor, leading to phosphorylation of Akt via a signaling cascade. Akt then activates phosphodiesterase 3B, resulting in conversion of cAMP to 5′-AMP and inactivation of PKA, which reduces HSL and PLIN1 phosphorylation and suppresses lipolysis. Akt-independent pathway may also mediate the antilipolytic activity of insulin [134]. During expression and enzymatic activity of MGL, the lipase that cleaves the last fatty acyl chain from monoacylglycerols does not seem to be affected by hormonal signals or the nutritional status [13].

Enhanced lipolysis and insulin resistance in obesity-associated NAFLD

Alterations in adipose lipolysis are expected to influence NAFLD by controlling blood levels of FFAs. Consistently, a recent exciting human genetic study has identified the critical role of HSL in regulating lipid and energy metabolism, as well as in the development of hepatic steatosis and type 2 diabetes [135]. In addition, studies of rare genetic diseases have established PLIN1, ATGL, and its coactivator, CGI-58, as key players in regulating adipose release of FFAs and “ectopic” fat deposition, including hepatic steatosis [65,136-138].

Insulin resistance is a pathological condition in which cells fail to respond to the normal actions of insulin. Insulin resistance is characterized by reduced efficiency of insulin to suppress hepatic glucose production and to stimulate glucose uptake in insulin-sensitive tissue. Epidemiological studies have shown that insulin resistance is more frequently seen in overweight individuals [139,140]. A study examined the correlation between body fat and “ectopic” lipid deposition in the liver and skeletal muscle of 314 subjects, in which both insulin resistance and fat mass positively correlate with liver fat [141]. Additionally, subjects with mutations in Akt2, a key kinase in the insulin-signaling pathway, exhibit insulin resistance and hepatic steatosis [142]. These observations demonstrate the key role of insulin resistance in hepatic steatosis and underlie the development of insulin sensitizers for the control of this liver disorder. Indeed, clinical improvement on insulin sensitivity by use of pioglitazone, a synthetic PPAR-γ agonist, lowers blood insulin levels and decreases hepatic fat [143].

Unanswered questions

Although NAFLDs are often associated with obesity, some obese subjects do not develop insulin resistance and NAFLD. About 35% of obese adults display normal intrahepatic TG content [4], and 2%-50% of obese adults are “metabolically normal” [144-150]. Molecular mechanisms for these observations are largely unknown. Although genetic landscape may shape the susceptibility of individuals to develop hepatic steatosis under various conditions [10], the interaction of genetics and epigenetics with environmental/metabolic cues to modulate NAFLD etiology is unknown. A recent study about the role of gut microbiota in NAFLD [151] further increases the complexity of molecular dissection of the pathogenesis of NAFLD. More importantly, we still do not understand the detailed mechanisms responsible for the progression of hepatic steatosis to NASH and fibrosis. Although “two hits” hypothesis was proposed to explain the etiology of NASH [152], the “two hits” likely include multiple hits. These “multiple hits” perhaps determine the fate of the disease, especially in obese individuals. Limiting these “hits” may not only slow down the progression but also induce the regression of NAFLD.

Conclusions

Chronic overnutrition and sedentary lifestyle drive the epidemic of central obesity in modern societies. As a result, the body has to adjust its metabolism and signaling pathways to compensate for these environmental cues. The duration of this compensatory period may depend on the interactions of multiple factors. When the causes continue to exist, compensatory mechanisms will fail, leading to common metabolic disorders, including insulin resistance and NAFLD. This failure in compensation at least includes lipotoxicity-associated damage of insulin signaling, mitochondrial overload, oxidative stress, and dysregulation of lipid transport and metabolism in adipose and nonadipose tissue. The crosstalk between fat and liver is obvious. Preventive and therapeutic approaches should focus on integrated pathophysiology of organ-organ communications.

References

[1] Fan JG, Zhu J, Li XJ, Chen L, Li L, Dai F, Li F, Chen SY. Prevalence of and risk factors for fatty liver in a general population of Shanghai, China. J Hepatol2005; 43(3): 508–514

[2] Fan JG. Epidemiology of alcoholic and nonalcoholic fatty liver disease in China. J Gastroenterol Hepatol2013; 28(Suppl 1): 11–17

[3] Masarone M, Federico A, Abenavoli L, Loguercio C, Persico M. Non alcoholic fatty liver: epidemiology and natural history. Rev Recent Clin Trials2014; 9(3): 126–133

[4] Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology2004; 40(6): 1387–1395

[5] Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA2010; 303(3): 235–241

[6] Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics2006; 118(4): 1388–1393

[7] Bellentani S, Scaglioni F, Marino M, Bedogni G. Epidemiology of non-alcoholic fatty liver disease. Dig Dis2010; 28(1): 155–161

[8] Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science2011; 332(6037): 1519–1523

[9] Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, Hobbs HH, Dobbins RL. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab2005; 288(2): E462–E468

[10] Hooper AJ, Adams LA, Burnett JR. Genetic determinants of hepatic steatosis in man. J Lipid Res2011; 52(4): 593–617

[11] Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology2005; 129(1): 113–121

[12] Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest2005; 115(5): 1343–1351

[13] Nielsen TS, Jessen N, Jørgensen JO, Møller N, Lund S. Dissecting adipose tissue lipolysis: molecular regulation and implications for metabolic disease. J Mol Endocrinol2014; 52(3): R199–R222

[14] Redgrave TG. Formation of cholesteryl ester-rich particulate lipid during metabolism of chylomicrons. J Clin Invest1970; 49(3): 465–471

[15] Falcon A, Doege H, Fluitt A, Tsang B, Watson N, Kay MA, Stahl A. FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain acyl-CoA synthetase. Am J Physiol Endocrinol Metab2010; 299(3): E384–E393

[16] Doege H, Baillie RA, Ortegon AM, Tsang B, Wu Q, Punreddy S, Hirsch D, Watson N, Gimeno RE, Stahl A. Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic lipid homeostasis. Gastroenterology2006; 130(4): 1245–1258

[17] Xu S, Jay A, Brunaldi K, Huang N, Hamilton JA. CD36 enhances fatty acid uptake by increasing the rate of intracellular esterification but not transport across the plasma membrane. Biochemistry2013; 52(41): 7254–7261

[18] Koonen DP, Jacobs RL, Febbraio M, Young ME, Soltys CL, Ong H, Vance DE, Dyck JR. Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity. Diabetes2007; 56(12): 2863–2871

[19] Su X, Abumrad NA. Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol Metab2009; 20(2): 72–77

[20] Mastrodonato M, Calamita G, Rossi R, Mentino D, Bonfrate L, Portincasa P, Ferri D, Liquori GE. Altered distribution of caveolin-1 in early liver steatosis. Eur J Clin Invest2011; 41(6): 642–651

[21] Fernández MA, Albor C, Ingelmo-Torres M, Nixon SJ, Ferguson C, Kurzchalia T, Tebar F, Enrich C, Parton RG, Pol A. Caveolin-1 is essential for liver regeneration. Science2006; 313(5793): 1628–1632

[22] Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov2008; 7(6): 489–503

[23] Queipo-Ortuño MI, Escoté X, Ceperuelo-Mallafré V, Garrido-Sanchez L, Miranda M, Clemente-Postigo M, Pérez-Pérez R, Peral B, Cardona F, Fernández-Real JM, Tinahones FJ, Vendrell J. FABP4 dynamics in obesity: discrepancies in adipose tissue and liver expression regarding circulating plasma levels. PLoS ONE2012; 7(11): e48605

[24] Berk PD. Regulatable fatty acid transport mechanisms are central to the pathophysiology of obesity, fatty liver, and metabolic syndrome. Hepatology2008; 48(5): 1362–1376

[25] Greco D, Kotronen A, Westerbacka J, Puig O, Arkkila P, Kiviluoto T, Laitinen S, Kolak M, Fisher RM, Hamsten A, Auvinen P, Yki-Järvinen H. Gene expression in human NAFLD. Am J Physiol Gastrointest Liver Physiol2008; 294(5): G1281–G1287

[26] Miquilena-Colina ME, Lima-Cabello E, Sánchez-Campos S, García-Mediavilla MV, Fernández-Bermejo M, Lozano-Rodríguez T, Vargas-Castrillón J, Buqué X, Ochoa B, Aspichueta P, González-Gallego J, García-Monzón C. Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. Gut2011; 60(10): 1394–1402

[27] Westerbacka J, Kolak M, Kiviluoto T, Arkkila P, Sirén J, Hamsten A, Fisher RM, Yki-Järvinen H. Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin-resistant subjects. Diabetes2007; 56(11): 2759–2765

[28] Lima-Cabello E, García-Mediavilla MV, Miquilena-Colina ME, Vargas-Castrillón J, Lozano-Rodríguez T, Fernández-Bermejo M, Olcoz JL, González-Gallego J, García-Monzón C, Sánchez-Campos S. Enhanced expression of pro-inflammatory mediators and liver X-receptor-regulated lipogenic genes in non-alcoholic fatty liver disease and hepatitis C. Clin Sci (Lond)2011; 120(6): 239–250

[29] Zelcer N, Tontonoz P. Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest2006; 116(3): 607–614

[30] Yang ZX, Shen W, Sun H. Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease. Hepatol Int2010; 4(4): 741–748

[31] Zhou J, Febbraio M, Wada T, Zhai Y, Kuruba R, He J, Lee JH, Khadem S, Ren S, Li S, Silverstein RL, Xie W. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology2008; 134(2): 556–567

[32] Memon RA, Tecott LH, Nonogaki K, Beigneux A, Moser AH, Grunfeld C, Feingold KR. Up-regulation of peroxisome proliferator-activated receptors (PPAR-α) and PPAR-γ messenger ribonucleic acid expression in the liver in murine obesity: troglitazone induces expression of PPAR-gamma-responsive adipose tissue-specific genes in the liver of obese diabetic mice. Endocrinology2000; 141(11): 4021–4031

[33] Foretz M, Guichard C, Ferré P, Foufelle F. Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. Proc Natl Acad Sci USA1999; 96(22): 12737–12742

[34] Ishii S, Iizuka K, Miller BC, Uyeda K. Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription. Proc Natl Acad Sci USA2004; 101(44): 15597–15602

[35] Yamashita H, Takenoshita M, Sakurai M, Bruick RK, Henzel WJ, Shillinglaw W, Arnot D, Uyeda K. A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver. Proc Natl Acad Sci USA2001; 98(16): 9116–9121

[36] Horton JD, Bashmakov Y, Shimomura I, Shimano H. Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice. Proc Natl Acad Sci USA1998; 95(11): 5987–5992

[37] Shimano H, Yahagi N, Amemiya-Kudo M, Hasty AH, Osuga J, Tamura Y, Shionoiri F, Iizuka Y, Ohashi K, Harada K, Gotoda T, Ishibashi S, Yamada N. Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes. J Biol Chem1999; 274(50): 35832–35839

[38] Shimomura I, Bashmakov Y, Ikemoto S, Horton JD, Brown MS, Goldstein JL. Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci USA1999; 96(24): 13656–13661

[39] Nohturfft A, DeBose-Boyd RA, Scheek S, Goldstein JL, Brown MS. Sterols regulate cycling of SREBP cleavage-activating protein (SCAP) between endoplasmic reticulum and Golgi. Proc Natl Acad Sci USA1999; 96(20): 11235–11240

[40] Sakai J, Nohturfft A, Cheng D, Ho YK, Brown MS, Goldstein JL. Identification of complexes between the COOH-terminal domains of sterol regulatory element-binding proteins (SREBPs) and SREBP cleavage-activating protein. J Biol Chem1997; 272(32): 20213–20221

[41] Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, Goldstein JL, Brown MS. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell2002; 110(4): 489–500

[42] Sun LP, Seemann J, Goldstein JL, Brown MS. Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins. Proc Natl Acad Sci USA2007; 104(16): 6519–6526

[43] Yellaturu CR, Deng X, Cagen LM, Wilcox HG, Mansbach CM 2nd, Siddiqi SA, Park EA, Raghow R, Elam MB. Insulin enhances post-translational processing of nascent SREBP-1c by promoting its phosphorylation and association with COPII vesicles. J Biol Chem2009; 284(12): 7518–7532

[44] Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest2002; 109(9): 1125–1131

[45] Shimomura I, Matsuda M, Hammer RE, Bashmakov Y, Brown MS, Goldstein JL. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cell2000; 6(1): 77–86

[46] Lee AH, Scapa EF, Cohen DE, Glimcher LH. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science2008; 320(5882): 1492–1496

[47] Lee JN, Ye J. Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1. J Biol Chem2004; 279(43): 45257–45265

[48] Kammoun HL, Chabanon H, Hainault I, Luquet S, Magnan C, Koike T, Ferré P, Foufelle F. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J Clin Invest2009; 119(5): 1201–1215

[49] Uyeda K, Repa JJ. Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab2006; 4(2): 107–110

[50] Ma L, Robinson LN, Towle HC. ChREBP*Mlx is the principal mediator of glucose-induced gene expression in the liver. J Biol Chem2006; 281(39): 28721–28730

[51] Iizuka K, Horikawa Y. ChREBP: a glucose-activated transcription factor involved in the development of metabolic syndrome. Endocr J2008; 55(4): 617–624

[52] Lindén D, William-Olsson L, Ahnmark A, Ekroos K, Hallberg C, Sjögren HP, Becker B, Svensson L, Clapham JC, Oscarsson J, Schreyer S. Liver-directed overexpression of mitochondrial glycerol-3-phosphate acyltransferase results in hepatic steatosis, increased triacylglycerol secretion and reduced fatty acid oxidation. FASEB J2006; 20(3): 434–443

[53] Agarwal AK, Arioglu E, De Almeida S, Akkoc N, Taylor SI, Bowcock AM, Barnes RI, Garg A. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet2002; 31(1): 21–23

[54] Choi CS, Savage DB, Kulkarni A, Yu XX, Liu ZX, Morino K, Kim S, Distefano A, Samuel VT, Neschen S, Zhang D, Wang A, Zhang XM, Kahn M, Cline GW, Pandey SK, Geisler JG, Bhanot S, Monia BP, Shulman GI. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem2007; 282(31): 22678–22688

[55] Diraison F, Moulin P, Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease. Diabetes Metab2003; 29(5): 478–485

[56] Gibbons GF, Wiggins D, Brown AM, Hebbachi AM. Synthesis and function of hepatic very-low-density lipoprotein. Biochem Soc Trans2004; 32(Pt 1): 59–64

[57] Hussain MM, Shi J, Dreizen P. Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res2003; 44(1): 22–32

[58] Ginsberg HN, Fisher EA. The ever-expanding role of degradation in the regulation of apolipoprotein B metabolism. J Lipid Res2009; 50(Suppl): S162–S166

[59] Kamagate A, Dong HH. FoxO1 integrates insulin signaling to VLDL production. Cell Cycle2008; 7(20): 3162–3170

[60] Tanoli T, Yue P, Yablonskiy D, Schonfeld G. Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity. J Lipid Res2004; 45(5): 941–947

[61] Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M, Wetterau JR. The role of the microsomal triglygeride transfer protein in abetalipoproteinemia. Annu Rev Nutr2000; 20(1): 663–697

[62] Bartels ED, Lauritsen M, Nielsen LB. Hepatic expression of microsomal triglyceride transfer protein and in vivo secretion of triglyceride-rich lipoproteins are increased in obese diabetic mice. Diabetes2002; 51(4): 1233–1239

[63] Higuchi N, Kato M, Tanaka M, Miyazaki M, Takao S, Kohjima M, Kotoh K, Enjoji M, Nakamuta M, Takayanagi R. Effects of insulin resistance and hepatic lipid accumulation on hepatic mRNA expression levels of apoB, MTP and L-FABP in non-alcoholic fatty liver disease. Exp Ther Med2011; 2(6): 1077–1081

[64] Wu JW, Wang SP, Alvarez F, Casavant S, Gauthier N, Abed L, Soni KG, Yang G, Mitchell GA. Deficiency of liver adipose triglyceride lipase in mice causes progressive hepatic steatosis. Hepatology2011; 54(1): 122–132

[65] Lass A, Zimmermann R, Haemmerle G, Riederer M, Schoiswohl G, Schweiger M, Kienesberger P, Strauss JG, Gorkiewicz G, Zechner R. Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome. Cell Metab2006; 3(5): 309–319

[66] Guo F, Ma Y, Kadegowda AK, Betters JL, Xie P, Liu G, Liu X, Miao H, Ou J, Su X, Zheng Z, Xue B, Shi H, Yu L. Deficiency of liver Comparative Gene Identification-58 causes steatohepatitis and fibrosis in mice. J Lipid Res2013; 54(8): 2109–2120

[67] Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet2008; 40(12): 1461–1465

[68] Zain SM, Mohamed R, Mahadeva S, Cheah PL, Rampal S, Basu RC, Mohamed Z. A multi-ethnic study of a PNPLA3 gene variant and its association with disease severity in non-alcoholic fatty liver disease. Hum Genet2012; 131(7): 1145–1152

[69] Smagris E, BasuRay S, Li J, Huang Y, Lai KM, Gromada J, Cohen JC, Hobbs HH. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology2015; 61(1): 108–118

[70] Berlanga A, Guiu-Jurado E, Porras JA, Auguet T. Molecular pathways in non-alcoholic fatty liver disease. Clin Exp Gastroenterol2014; 7: 221–239

[71] Jogl G, Hsiao YS, Tong L. Structure and function of carnitine acyltransferases. Ann N Y Acad Sci2004; 1033(1): 17–29

[72] Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, Milne JC, Lambert PD, Mataki C, Elliott PJ, Auwerx J. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab2008; 8(5): 347–358

[73] Guarente L. Sirtuins as potential targets for metabolic syndrome. Nature2006; 444(7121): 868–874

[74] Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol2015; 62(3): 720–733

[75] Rodgers JT, Puigserver P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci USA2007; 104(31): 12861–12866

[76] Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab2009; 9(4): 327–338

[77] Xu F, Gao Z, Zhang J, Rivera CA, Yin J, Weng J, Ye J. Lack of SIRT1 (Mammalian Sirtuin 1) activity leads to liver steatosis in the SIRT1^+/- mice: a role of lipid mobilization and inflammation. Endocrinology2010; 151(6): 2504–2514

[78] Li Y, Xu S, Giles A, Nakamura K, Lee JW, Hou X, Donmez G, Li J, Luo Z, Walsh K, Guarente L, Zang M. Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver. FASEB J2011; 25(5): 1664–1679

[79] Ponugoti B, Kim DH, Xiao Z, Smith Z, Miao J, Zang M, Wu SY, Chiang CM, Veenstra TD, Kemper JK. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J Biol Chem2010; 285(44): 33959–33970

[80] Li Y, Wong K, Giles A, Jiang J, Lee JW, Adams AC, Kharitonenkov A, Yang Q, Gao B, Guarente L, Zang M. Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21. Gastroenterology2014; 146(2): 539–49.e7

[81] Chakrabarti P, English T, Karki S, Qiang L, Tao R, Kim J, Luo Z, Farmer SR, Kandror KV. SIRT1 controls lipolysis in adipocytes via FOXO1-mediated expression of ATGL. J Lipid Res2011; 52(9): 1693–1701

[82] Gao Z, Zhang J, Kheterpal I, Kennedy N, Davis RJ, Ye J. Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun N-terminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity. J Biol Chem2011; 286(25): 22227–22234

[83] Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE, Mangelsdorf DJ, Kliewer SA. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab2007; 5(6): 415–425

[84] Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, Moller DE, Kharitonenkov A. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology2008; 149(12): 6018–6027

[85] Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, Gromada J, Brozinick JT, Hawkins ED, Wroblewski VJ, Li DS, Mehrbod F, Jaskunas SR, Shanafelt AB. FGF-21 as a novel metabolic regulator. J Clin Invest2005; 115(6): 1627–1635

[86] Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, Mohammadi M, Finck BN, Mangelsdorf DJ, Kliewer SA, Burgess SC. FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci USA2009; 106(26): 10853–10858

[87] Kliewer SA, Mangelsdorf DJ. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr2010; 91(1): 254S–257S

[88] Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med2002; 53(1): 409–435

[89] Karpe F, Ehrenborg EE. PPARδ in humans: genetic and pharmacological evidence for a significant metabolic function. Curr Opin Lipidol2009; 20(4): 333–336

[90] Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology2010; 52(1): 79–104

[91] Ratziu V. Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol2013; 10(11): 676–685

[92] Kohjima M, Enjoji M, Higuchi N, Kato M, Kotoh K, Yoshimoto T, Fujino T, Yada M, Yada R, Harada N, Takayanagi R, Nakamuta M. Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. Int J Mol Med2007; 20(3): 351–358

[93] Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res2009; 48(1): 1–26

[94] Kotronen A, Seppälä-Lindroos A, Vehkavaara S, Bergholm R, Frayn KN, Fielding BA, Yki-Järvinen H. Liver fat and lipid oxidation in humans. Liver Int2009; 29(9): 1439–1446

[95] Croci I, Byrne NM, Choquette S, Hills AP, Chachay VS, Clouston AD, O’Moore-Sullivan TM, Macdonald GA, Prins JB, Hickman IJ. Whole-body substrate metabolism is associated with disease severity in patients with non-alcoholic fatty liver disease. Gut2013; 62(11): 1625–1633

[96] Fabbrini E, Mohammed BS, Korenblat KM, Magkos F, McCrea J, Patterson BW, Klein S. Effect of fenofibrate and niacin on intrahepatic triglyceride content, very low-density lipoprotein kinetics, and insulin action in obese subjects with nonalcoholic fatty liver disease. J Clin Endocrinol Metab2010; 95(6): 2727–2735

[97] Szabo G, Bala S. MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol2013; 10(9): 542–552

[98] Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T. Identification of tissue-specific microRNAs from mouse. Curr Biol2002; 12(9): 735–739

[99] Chang J, Nicolas E, Marks D, Sander C, Lerro A, Buendia MA, Xu C, Mason WS, Moloshok T, Bort R, Zaret KS, Taylor JM. miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1. RNA Biol2004; 1(2): 106–113

[100] Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, Watts L, Booten SL, Graham M, McKay R, Subramaniam A, Propp S, Lollo BA, Freier S, Bennett CF, Bhanot S, Monia BP. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab2006; 3(2): 87–98

[101] Krützfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M. Silencing of microRNAs in vivo with ‘antagomirs’. Nature2005; 438(7068): 685–689

[102] Pirola CJ, Fernandez GT, Castano GO, Mallardi P, San MJ, Mora GLLM, Flichman D, Mirshahi F, Sanyal AJ, Sookoian S. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut2015; 64(5): 800–812.

[103] Cheung O, Puri P, Eicken C, Contos MJ, Mirshahi F, Maher JW, Kellum JM, Min H, Luketic VA, Sanyal AJ. Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression. Hepatology2008; 48(6): 1810–1820

[104] Hsu SH, Wang B, Kota J, Yu J, Costinean S, Kutay H, Yu L, Bai S, La Perle K, Chivukula RR, Mao H, Wei M, Clark KR, Mendell JR, Caligiuri MA, Jacob ST, Mendell JT, Ghoshal K. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J Clin Invest2012; 122(8): 2871–2883

[105] Tsai WC, Hsu SD, Hsu CS, Lai TC, Chen SJ, Shen R, Huang Y, Chen HC, Lee CH, Tsai TF, Hsu MT, Wu JC, Huang HD, Shiao MS, Hsiao M, Tsou AP. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest2012; 122(8): 2884–2897

[106] Horie T, Nishino T, Baba O, Kuwabara Y, Nakao T, Nishiga M, Usami S, Izuhara M, Sowa N, Yahagi N, Shimano H, Matsumura S, Inoue K, Marusawa H, Nakamura T, Hasegawa K, Kume N, Yokode M, Kita T, Kimura T, Ono K. MicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice. Nat Commun2013; 4: 2883

[107] Lee J, Padhye A, Sharma A, Song G, Miao J, Mo YY, Wang L, Kemper JK. A pathway involving farnesoid X receptor and small heterodimer partner positively regulates hepatic sirtuin 1 levels via microRNA-34a inhibition. J Biol Chem2010; 285(17): 12604–12611

[108] Iliopoulos D, Drosatos K, Hiyama Y, Goldberg IJ, Zannis VI. MicroRNA-370 controls the expression of microRNA-122 and Cpt1α and affects lipid metabolism. J Lipid Res2010; 51(6): 1513–1523

[109] Ou Z, Wada T, Gramignoli R, Li S, Strom SC, Huang M, Xie W. MicroRNA hsa-miR-613 targets the human LXRα gene and mediates a feedback loop of LXRα autoregulation. Mol Endocrinol2011; 25(4): 584–596

[110] Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ. Autophagy regulates lipid metabolism. Nature2009; 458(7242): 1131–1135

[111] Yang L, Li P, Fu S, Calay ES, Hotamisligil GS. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab2010; 11(6): 467–478

[112] Lavallard VJ, Gual P. Autophagy and non-alcoholic fatty liver disease. Biomed Res Int 2014; 2014: 120179

[113] Meijer AJ. Amino acid regulation of autophagosome formation. Methods Mol Biol2008; 445: 89–109

[114] Inami Y, Yamashina S, Izumi K, Ueno T, Tanida I, Ikejima K, Watanabe S. Hepatic steatosis inhibits autophagic proteolysis via impairment of autophagosomal acidification and cathepsin expression. Biochem Biophys Res Commun2011; 412(4): 618–625

[115] Fukuo Y, Yamashina S, Sonoue H, Arakawa A, Nakadera E, Aoyama T, Uchiyama A, Kon K, Ikejima K, Watanabe S. Abnormality of autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease. Hepatol Res2014; 44(9): 1026–1036

[116] Mummadi RR, Kasturi KS, Chennareddygari S, Sood GK. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol2008; 6(12): 1396–1402

[117] Johnson NA, George J. Fitness versus fatness: moving beyond weight loss in nonalcoholic fatty liver disease. Hepatology2010; 52(1): 370–381

[118] Zechner R, Strauss JG, Haemmerle G, Lass A, Zimmermann R. Lipolysis: pathway under construction. Curr Opin Lipidol2005; 16(3): 333–340

[119] Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, Lass A, Neuberger G, Eisenhaber F, Hermetter A, Zechner R. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science2004; 306(5700): 1383–1386

[120] Kraemer FB, Shen WJ. Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis. J Lipid Res2002; 43(10): 1585–1594

[121] Karlsson M, Contreras JA, Hellman U, Tornqvist H, Holm C. cDNA cloning, tissue distribution, and identification of the catalytic triad of monoglyceride lipase. Evolutionary relationship to esterases, lysophospholipases, and haloperoxidases. J Biol Chem1997; 272(43): 27218–27223

[122] Greenberg AS, Egan JJ, Wek SA, Garty NB, Blanchette-Mackie EJ, Londos C. Perilipin, a major hormonally regulated adipocyte-specific phosphoprotein associated with the periphery of lipid storage droplets. J Biol Chem1991; 266(17): 11341–11346

[123] Subramanian V, Rothenberg A, Gomez C, Cohen AW, Garcia A, Bhattacharyya S, Shapiro L, Dolios G, Wang R, Lisanti MP, Brasaemle DL. Perilipin A mediates the reversible binding of CGI-58 to lipid droplets in 3T3-L1 adipocytes. J Biol Chem2004; 279(40): 42062–42071

[124] Yamaguchi T, Omatsu N, Matsushita S, Osumi T. CGI-58 interacts with perilipin and is localized to lipid droplets. Possible involvement of CGI-58 mislocalization in Chanarin-Dorfman syndrome. J Biol Chem2004; 279(29): 30490–30497

[125] Granneman JG, Moore HP, Granneman RL, Greenberg AS, Obin MS, Zhu Z. Analysis of lipolytic protein trafficking and interactions in adipocytes. J Biol Chem2007; 282(8): 5726–5735

[126] Granneman JG, Moore HP, Krishnamoorthy R, Rathod M. Perilipin controls lipolysis by regulating the interactions of AB-hydrolase containing 5 (Abhd5) and adipose triglyceride lipase (Atgl). J Biol Chem2009; 284(50): 34538–34544

[127] Yang X, Lu X, Lombès M, Rha GB, Chi YI, Guerin TM, Smart EJ, Liu J. The G(0)/G(1) switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase. Cell Metab2010; 11(3): 194–205

[128] Wang Y, Zhang Y, Qian H, Lu J, Zhang Z, Min X, Lang M, Yang H, Wang N, Zhang P. The G₀/G_{<?Pub Caret?>1} switch gene 2 is an important regulator of hepatic triglyceride metabolism. PLoS ONE2013; 8(8): e72315

[129] Xu L, Zhou L, Li P. CIDE proteins and lipid metabolism. Arterioscler Thromb Vasc Biol2012; 32(5): 1094–1098

[130] Rubio-Cabezas O, Puri V, Murano I, Saudek V, Semple RK, Dash S, Hyden CS, Bottomley W, Vigouroux C, Magré J, Raymond-Barker P, Murgatroyd PR, Chawla A, Skepper JN, Chatterjee VK, Suliman S, Patch AM, Agarwal AK, Garg A, Barroso I, Cinti S, Czech MP, Argente J, O’Rahilly S, Savage DB; LD Screening Consortium.Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Mol Med2009; 1(5): 280–287

[131] Puri V, Ranjit S, Konda S, Nicoloro SM, Straubhaar J, Chawla A, Chouinard M, Lin C, Burkart A, Corvera S, Perugini RA, Czech MP. Cidea is associated with lipid droplets and insulin sensitivity in humans. Proc Natl Acad Sci USA2008; 105(22): 7833–7838

[132] Shen WJ, Patel S, Miyoshi H, Greenberg AS, Kraemer FB. Functional interaction of hormone-sensitive lipase and perilipin in lipolysis. J Lipid Res2009; 50(11): 2306–2313

[133] Wang H, Hu L, Dalen K, Dorward H, Marcinkiewicz A, Russell D, Gong D, Londos C, Yamaguchi T, Holm C, Rizzo MA, Brasaemle D, Sztalryd C. Activation of hormone-sensitive lipase requires two steps, protein phosphorylation and binding to the PAT-1 domain of lipid droplet coat proteins. J Biol Chem2009; 284(46): 32116–32125

[134] Chakrabarti P, Kim JY, Singh M, Shin YK, Kim J, Kumbrink J, Wu Y, Lee MJ, Kirsch KH, Fried SK, Kandror KV. Insulin inhibits lipolysis in adipocytes via the evolutionarily conserved mTORC1-Egr1-ATGL-mediated pathway. Mol Cell Biol2013; 33(18): 3659–3666

[135] Albert JS, Yerges-Armstrong LM, Horenstein RB, Pollin TI, Sreenivasan UT, Chai S, Blaner WS, Snitker S, O’Connell JR, Gong DW, Breyer RJ 3rd, Ryan AS, McLenithan JC, Shuldiner AR, Sztalryd C, Damcott CM. Null mutation in hormone-sensitive lipase gene and risk of type 2 diabetes. N Engl J Med2014; 370(24): 2307–2315

[136] Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y, Charpentier G, Auclair M, Delépine M, Barroso I, Semple RK, Lathrop M, Lascols O, Capeau J, O’Rahilly S, Magré J, Savage DB, Vigouroux C. Perilipin deficiency and autosomal dominant partial lipodystrophy. N Engl J Med2011; 364(8): 740–748

[137] Gandotra S, Lim K, Girousse A, Saudek V, O’Rahilly S, Savage DB. Human frame shift mutations affecting the carboxyl terminus of perilipin increase lipolysis by failing to sequester the adipose triglyceride lipase (ATGL) coactivator AB-hydrolase-containing 5 (ABHD5). J Biol Chem2011; 286(40): 34998–35006

[138] Schweiger M, Lass A, Zimmermann R, Eichmann TO, Zechner R. Neutral lipid storage disease: genetic disorders caused by mutations in adipose triglyceride lipase/PNPLA2 or CGI-58/ABHD5. Am J Physiol Endocrinol Metab2009; 297(2): E289–E296

[139] McLaughlin T, Abbasi F, Cheal K, Chu J, Lamendola C, Reaven G. Use of metabolic markers to identify overweight individuals who are insulin resistant. Ann Intern Med2003; 139(10): 802–809

[140] McLaughlin T, Allison G, Abbasi F, Lamendola C, Reaven G. Prevalence of insulin resistance and associated cardiovascular disease risk factors among normal weight, overweight, and obese individuals. Metabolism2004; 53(4): 495–499

[141] Stefan N, Kantartzis K, Machann J, Schick F, Thamer C, Rittig K, Balletshofer B, Machicao F, Fritsche A, Häring HU. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med2008; 168(15): 1609–1616

[142] Semple RK, Sleigh A, Murgatroyd PR, Adams CA, Bluck L, Jackson S, Vottero A, Kanabar D, Charlton-Menys V, Durrington P, Soos MA, Carpenter TA, Lomas DJ, Cochran EK, Gorden P, O’Rahilly S, Savage DB. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J Clin Invest2009; 119(2): 315–322

[143] Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med2010; 362(18): 1675–1685

[144] Calori G, Lattuada G, Piemonti L, Garancini MP, Ragogna F, Villa M, Mannino S, Crosignani P, Bosi E, Luzi L, Ruotolo G, Perseghin G. Prevalence, metabolic features, and prognosis of metabolically healthy obese Italian individuals: the Cremona Study. Diabetes Care2011; 34(1): 210–215

[145] Hamer M, Stamatakis E. Metabolically healthy obesity and risk of all-cause and cardiovascular disease mortality. J Clin Endocrinol Metab2012; 97(7): 2482–2488

[146] Lopez-Garcia E, Guallar-Castillon P, Leon-Muñoz L, Rodriguez-Artalejo F. Prevalence and determinants of metabolically healthy obesity in Spain. Atherosclerosis2013; 231(1): 152–157

[147] Shea JL, Randell EW, Sun G. The prevalence of metabolically healthy obese subjects defined by BMI and dual-energy X-ray absorptiometry. Obesity (Silver Spring)2011; 19(3): 624–630

[148] van Vliet-Ostaptchouk JV, Nuotio ML, Slagter SN, Doiron D, Fischer K, Foco L, Gaye A, Gögele M, Heier M, Hiekkalinna T, Joensuu A, Newby C, Pang C, Partinen E, Reischl E, Schwienbacher C, Tammesoo ML, Swertz MA, Burton P, Ferretti V, Fortier I, Giepmans L, Harris JR, Hillege HL, Holmen J, Jula A, Kootstra-Ros JE, Kvaløy K, Holmen TL, Männistö S, Metspalu A, Midthjell K, Murtagh MJ, Peters A, Pramstaller PP, Saaristo T, Salomaa V, Stolk RP, Uusitupa M, van der Harst P, van der Klauw MM, Waldenberger M, Perola M, Wolffenbuttel BH. The prevalence of metabolic syndrome and metabolically healthy obesity in Europe: a collaborative analysis of ten large cohort studies. BMC Endocr Disord2014; 14(1): 9

[149] Durward CM, Hartman TJ, Nickols-Richardson SM. All-cause mortality risk of metabolically healthy obese individuals in NHANES III. J Obes 2012; 2012: 460321

[150] Pajunen P, Kotronen A, Korpi-Hyövälti E, Keinänen-Kiukaanniemi S, Oksa H, Niskanen L, Saaristo T, Saltevo JT, Sundvall J, Vanhala M, Uusitupa M, Peltonen M. Metabolically healthy and unhealthy obesity phenotypes in the general population: the FIN-D2D Survey. BMC Public Health2011; 11(1): 754

[151] Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature2012; 482(7384): 179–185

[152] Day CP. Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol2002; 16(5): 663–678

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag Berlin Heidelberg