REVIEW Animal Cells and Systems, 2014 Vol. 18, No. 2, 77–82, http://dx.doi.org/10.1080/19768354.2014.906502 a b,c a* b,c,d* Yoo Jeong Lee , Jung Hwan Yu , Won-Ho Kim and Jae-woo Kim Division of Metabolic Disease, Center for Biomedical Sciences, National Institutes of Health, Cheongwon-gun, Chungbuk 363-951, Korea; Department of Biochemistry and Molecular Biology, Integrated Genomic Research Center for Metabolic Regulation, Institute of Genetic Science, Yonsei University College of Medicine, Seoul 120-752, Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea; Department of Integrated OMICS for Biomedical Sciences, Graduate School, Yonsei University College of Medicine, Seoul 120-749, Korea (Received 16 March 2014; received in revised form 17 March 2014; accepted 17 March 2014) Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease and can lead to hepatic cirrhosis with liver failure. NAFLD is common in individuals who have obesity, diabetes, dyslipidemia, and/or hypertension. NAFLD comprises a wide spectrum of liver lesions ranging from mild hepatic steatosis to nonalcoholic steatohepatitis (NASH), the most aggressive form. Hepatic steatosis, also called fatty liver, is the hallmark of NAFLD and is defined as excess intrahepatic triglyceride (TG) content (≥5% of liver volume or weight). In some cases, the fat accumulation is associated with steatohepatitis, inflammation, and fibrous change of the liver. Studies on the regulation of de novo fatty acid synthesis have revealed the mechanism leading to hepatic steatosis, mostly emphasizing the roles of transcriptional regulation of enzymes involved in lipid metabolic pathway. Recently, high-fat diet-induced hepatic lipid accumulation has also been associated with hepatocyte uptake of fatty acids from lipolyzed TG in adipose tissue, as well as hepatic TG incorporation. This review discusses a conceptual framework of how hepatic TG accumulation contributes to hepatic steatosis. Keywords: nonalcoholic fatty liver disease; hepatic steatosis; lipid accumulation; PPARγ, MGAT1 Introduction Because the liver does not act as a primary fat storage depot, the steady state concentration of hepatic TGs is low Metabolic syndrome is characterized by central obesity, under normal physiological conditions. However, over- dyslipidemia, hypertension, and insulin resistance (Kopel- eating and lack of exercise cause the liver to store excess man 2000). Nonalcoholic fatty liver disease (NAFLD) is energy as TG. Fat accumulation in the hepatocytes occurs frequently observed in subjects with metabolic syndrome when the rate of hepatic fatty acid uptake from plasma or in the absence of alcohol abuse (Marchesini et al. 2001) de novo fatty acid synthesis is greater than the rate of fatty and consists of differentially graded liver lesions ranging acid oxidation and export of hepatic TG via very low from intrahepatic fat accumulation to steatohepatitis, density lipoproteins (VLDLs). Once taken up by hepato- eventually leading to fibrosis and cirrhosis (Angulo cytes, FFAs either undergo oxidation in mitochondria, 2002). According to the “two-hit” model theory of peroxisomes, or microsomes, or they become esterified NAFLD progression (Day & James 1998), the “first hit” and exit the liver as VLDL-TG. The major sources of consists of hepatic fat accumulation and the predisposition hepatic fatty acids for TG assembly are those synthesized for hepatocyte injury to develop. Obesity and insulin de novo in the liver and those derived from plasma. resistance are characterized by an increased influx of free Elevated plasma FFA increases their delivery to the liver, fatty acids (FFAs) to the liver (Adams et al. 2009; Brunt which may cause excessive hepatic TG accumulation even 2010) and may contribute to excessive hepatic fat accu- if fatty acid oxidation increases. It was demonstrated that mulation. Under normal circumstances, FFAs taken up by of the TG in the liver, 60% come from FFA, 26% from de the liver either undergo β-oxidation or are re-esterified novo lipogenesis, and 14% from the diet (Donnelly et al. with glycerol to form triglycerides (TGs), preventing toxic 2005), indicating that FFA release from adipose tissue effects. However, when excess FFAs are produced by the lipolysis in adipose tissue, hepatocytes accumulate a large may be a major contributor to obesity-related NAFLD. Because the liver is a major regulator of whole-body amount of fat droplets in their cytoplasm, causing hepatic lipid metabolism, it has a high capacity for the uptake of steatosis. The “second hit” of the progression to nonalco- holic steatohepatitis (NASH) consists of oxidative stress various materials from the circulation and secretion. This and subsequent lipid peroxidation, proinflammatory review will focus on the molecular mechanisms involved cytokines, adipokines, and mitochondrial dysfunction in the development of hepatic steatosis and potential (Qureshi & Abrams 2007). therapeutic options for treatment. *Corresponding authors. Emails: email@example.com; firstname.lastname@example.org © 2014 Korean Society for Integrative Biology 78 Y.J. Lee et al. Hepatic steatosis in metabolic syndrome Ceramides may play a role in the pathogenesis of insulin resistance. When fatty acids are taken up by liver, About 75% of hepatic steatosis cases occur in obese people they are rapidly esterified to fatty acyl CoAs. Serine (Hamaguchi et al. 2005). Because high-fat diets often result palmitoyltransferase (SPT)1 catalyzes the conversion of in excess caloric intake, which eventually leads to obesity, fatty acyl CoAs to sphingosine, which is metabolized to the effects of a high-fat diet on hepatic fat accumulation ceramide (Hannun & Obeid 2002). Along with DAG, should not be ignored. Insulin resistance is the most intracellular ceramide is increased in obese animal models common characteristic of subjects with obesity and type 2 (Turinsky et al. 1990), and blocking SPT1 enzyme activity diabetes and also plays a key role in hepatic lipid accumu- improves insulin resistance and ameliorates the ceramide lation (Bugianesi et al. 2005), as the excess visceral fat increase in steatotic muscle and liver. characteristic of insulin resistance may be a major contrib- utor to hepatic steatosis (Ruhl & Everhart 2003). TG is hydrolyzed in a reaction catalyzed by adipose Metabolic pathways in hepatic lipid accumulation triglyceride lipase (ATGL) and hormone-sensitive lipase Fatty acid uptake (HSL), which are both regulated by glucagon and cAMP FFAs released from adipose tissue are bound to serum signaling (Watt & Steinberg 2008). Insulin reciprocally albumin and transported to the liver via the portal inhibits this process, resulting in decrease of TG lipolysis. circulation. The FFAs transported into the cell are Because insulin resistance impairs this physiologic sup- converted to acyl CoAs, which are trapped in the plasma pression of lipolysis, obese people with excess visceral fat membrane and unable to efflux from the cell. Fatty acid show increased lipolytic activity. This triggers the release transport proteins (FATPs), fatty acid translocase (FAT)/ of FFA into the portal vein, which is then delivered to the CD36, and fatty acid-binding protein (FABP) play dom- liver. Because approximately 60% of liver TG is derived inant roles in transmembrane trafficking of fatty acids from circulating FFA, increased lipolysis is likely the (McArthur et al. 1999). FAT/CD36, primarily expressed in primary source of lipids contributing to steatosis in adipose tissue, is a membrane-bound translocase that individuals with visceral obesity. facilitates FFA uptake into the cell via diffusion and Increased FFAs in the liver may induce hepatic insulin intracellular trafficking (Abumrad et al. 1993). Although resistance, although the mechanisms through which this FAT/CD36 expression level is typically low in hepato- occurs remain to be clarified. Lipid signaling intermedi- cytes, it is increased with diet-induced obesity (Lee et al. ates likely play a role. Diacylglycerols, ceramides, and 2012). Additionally, hepatic steatosis is largely abolished phosphoinositol 3-phosphate normally exist at a certain in CD36 knockout mice (Zhou et al. 2008), suggesting level either in plasma or cells, and they stimulate cells to that aberrant expression of CD36, along with the resulting store lipids and protect the body from a toxic condition. increase in FFA uptake in liver, may promote development or increase the severity of hepatic steatosis. Therefore, investigating the roles of lipid signaling inter- FATPs possess fatty acyl CoA synthetase activity, as mediates in the development of hepatic steatosis is they convert fatty acids into fatty acyl CoA. Among the important, particularly if the intermediates are involved six isoforms identified in mammals, FATP2 and FATP5 in hepatic insulin resistance. Cellular TG accumulation per are expressed in liver. In mouse hepatocytes, knockdown se does not initially damage hepatocytes and actually of FATP5 markedly reduces hepatic dietary fatty acid protects cells from lipotoxicity (Listenberger et al. 2003; uptake and TG accumulation (Doege et al. 2008). Yamaguchi et al. 2007). Blocking diacylglycerol acyl- Similarly, liver-specific FABP knockout mice are pro- transferase 2 (DGAT2), one of the main enzymes involved tected against diet-induced obesity and show altered FA in TG incorporation, improves steatosis but increases trafficking as well as reduced hepatic FA uptake, resulting hepatocyte damage (Yamaguchi et al. 2007). This is not in decreased hepatic steatosis (Newberry et al. 2006). surprising because lipid metabolites, such as ceramide and Thus, increased fatty acid flux in the high-glucagon state, diacylglycerol (DAG), are implicated in the pathogenesis either in insulin resistance or the fasting condition, of insulin resistance (Samuel & Shulman 2012). In contributes to diet-induced hepatic steatosis. another study, however, suppression of DGAT2 reversed diet-induced hepatic steatosis and insulin resistance, with unexpectedly low level of DAG (Choi et al. 2007). This De novo fatty acid synthesis controversy may indicate that DAG and/or other lipid Under normal conditions, excess glucose is metabolized to intermediates, but not TG, are involved in hepatic insulin form acetyl CoA, converted to malonyl CoA by acetyl resistance, but the experimental results should be inter- CoA carboxylase (ACC), and then undergoes de novo preted carefully. Nevertheless, these results suggest that fatty acid synthesis by the concerted actions of fatty acid simply inhibiting TG synthesis may not be a good strategy synthase (FAS), ATP citrate lyase (ACL), long-chain for the treatment of NAFLD. elongase (ELOVL), and stearoyl CoA desaturase 1 Animal Cells and Systems 79 (SCD1). These FFAs synthesized from glucose account Insulin, glucose, and lipid signals with transcriptional for 26% of hepatic TG accumulation and may contribute regulation in liver to NAFLD (Donnelly et al. 2005). The regulation of de SREBP-1c and insulin signaling novo fatty acid synthesis has been extensively investi- SREBPs, membrane-bound transcription factors of the gated, revealing the roles of several important transcrip- basic-helix-loop-helix-leucine zipper (bHLH-Zip) family, tion factors, such as sterol regulatory element binding regulate enzymes involved in homeostatic regulation of protein (SREBP)-1c and carbohydrate response element cholesterol and lipid metabolism (Horton et al. 2002). binding protein (ChREBP). Expression of SREBP-1c and SREBP-1c increases the expression of genes involved in ChREBP, and thereby de novo fatty acid synthesis, is de novo fatty acid synthesis, whereas SREBP-2 activates increased in response to elevated insulin and glucose genes associated with cholesterol synthesis. SREBP-1c levels, respectively (Postic & Girard 2008). Although and its target genes are increased in fatty liver disease, and research on hepatic steatosis has been largely focused on overexpression of SREBP-1c leads to TG accumulation in the transcriptional control of fatty acid synthesis enzymes, the liver without increasing cholesterol (Shimomura et al. it may not account for increased hepatic lipids associated 1999; Knebel et al. 2012). SREBP-1c is expressed as an with diet-induced hepatic steatosis. inactive precursor molecule bound on the endoplasmic reticulum membrane until proteolytic machinery involved in sterol-related regulation releases a nuclear active form. TG synthesis Transcription of SREBP-1c is also stimulated by insulin and inhibited by glucagon (Foretz et al. 1999). Thus, Once fatty acids are converted into acyl CoAs by acyl SREBP-1c is markedly reduced by fasting and elevated CoA synthetase in the liver, they undergo a series of following high-carbohydrate feeding in animals. reactions leading to TG synthesis through two major The effect of insulin on SREBP-1c expression is pathways. The classic glycerol 3-phosphate pathway mediated by the PI3K, Akt, and mTORC1 dependent begins with the acylation of glycerol-3-phosphate with pathway (Fleischmann & Iynedjian 2000; Owen et al. a fatty acyl CoA by glycerol-3-phosphate acyltransferase 2012). SREBP-1c transcription may also be induced by (GPAT). The resulting lysophosphatidic acid is further the activation of Liver X Receptor (LXR) α and is important acylated and dephosphorylated by 1-acylglycerol-3- for maintaining basal transcription levels of ACC, FAS, and phosphate acyltransferase (AGPAT) and Lipin, respect- SCD-1 (Liang et al. 2002). SREBP-1c expression is ively, to produce diacylglycerol (DAG). The other increased in the fatty livers of obese, insulin-resistant, and pathway, known as monoacylglycerol pathway, begins hyperinsulinemic mice, whereas knockout SREBP-1 in ob/ with the acylation of MAG with a fatty acyl CoA by ob mice exhibit reduced lipogenic gene expression, and monoacylglycerol acyltransferase (MGAT), resulting in thereby decreased hepatic steatosis. Therefore, SREBP-1c is formation of DAG. The final step for converting DAG to one of the main transcription factors regulating hepatic lipid TG by DGAT1 or DGAT2 is common in both pathways. accumulation primarily in response to insulin and the fed In obesity-induced hepatic steatosis, FFAs from adipose state and is associated with NAFLD (Figure 1). tissue or dietary fat directly can enter TG synthesis pathway, probably through the classic glycerol 3-phos- phate pathway. It is uncertain how much MAGs are ChREBP and glucose signaling directly transported into hepatocytes. In this regard, it is Expression of hepatic ChREBP, which promotes conver- surprising that adenovirus-mediated MGAT1 suppression sion of excess carbohydrate to lipid in the liver, is induced dramatically improves hepatic steatosis associated with in response to high-carbohydrate diet but not to fasting or diet-induced obesity (Lee et al. 2012). MGAT1 expres- a high-fat diet (Benhamed et al. 2012). When glucose sion is induced by peroxisome proliferator-activated levels are low, ChREBP is phosphorylated by cAMP receptor (PPAR)γ, which is aberrantly overexpressed in dependent protein kinase (PK-A) and located in the steatotic liver. Although the mechanism by which cytosol. High glucose concentration promotes depho- MGAT1 inhibition improves hepatic steatosis is not fully sphorylation of ChREBP, which results in its entry into understood, monoacylglycerol may be involved in the the nucleus and binding as a heterotetramer with Max like re-esterification process after lipolysis. It was reported protein (Mlx) on the E boxes. ChREBP is also a direct that a considerable proportion of fatty acids derived from target gene of LXRs and regulates L-pyruvate kinase (L- lipolysis is re-esterified into TG (Campbell et al. 1992). PK), FAS, and ACC genes in response to glucose (Ishii Whether MGAT1 expressed in steatotic liver rapidly et al. 2004). Liver-specific inhibition of ChREBP sig- re-esterifies MAG and fatty acids, and thereby aggra- nificantly reduces the expression of L-PK, ACC, and FAS; vates lipid accumulation, should be investigated in future decreases hepatic fat accumulation; and restores insulin studies. sensitivity in liver. Thus, ChREBP activity increases in 80 Y.J. Lee et al. Figure 1. Transcriptional regulation of hepatic TG accumulation and its involvement in hepatic steatosis. Free fatty acids can be synthesized de novo from glucose, mainly regulated by SREBP-1c and ChREBP. Upon a high-fat diet, increased plasma free fatty acids are delivered to liver, either from diet or adipose tissue, which contributes the development and/or aggravation of fatty liver. In this situation, some of lipid metabolites may trigger the expression of PPARγ, which in turn induces the gene expression involved in fatty acid uptake (CD36, FATP, and FABP4) as well as alternative TG synthesis pathway (LPP, MGAT1, and ADRP). Consequently, the incorporation of fatty acyl CoA into TG is greatly enhanced and the machinery of lipid accumulation now mimics that of adipose tissue. GK, glucokinase; L-PK, liver type pyruvate kinase; ACC, acetyl CoA carboxylase; FAS, fatty acid synthase; SCD1, stearyl CoA desaturase; ACS, acyl Co-A synthetase; DAG, diacylglycerol; G3P, glycerol-3-phosphate; GPAT, glycerol-3-phosphate acyltransferases; LPA, lysophosphatidic acid; LPP, lipid phosphate phosphatase, MAG, monoacylglycerol; PA, phosphatidic acid; ADRP, adipose differentiation-related protein. response to high glucose in metabolic diseases and is is associated with genes involved in fatty acid transport and associated with development of fatty liver (Figure 1). TG synthesis. With a high-fat diet, PPARγ transcription is upregulated, resulting in the induction of FABP and CD36 genes and increased fatty acid uptake. Moreover, hepatic PPARγ and lipid signaling PPARγ stimulates the expression of genes involved in TG synthesis, including MGAT1, adipose differentiation- PPARγ, a ligand-activated transcription factor that belongs related protein (ADRP), and fat specific protein 27 to a member of the nuclear receptor superfamily, has long (FSP27; Lee et al. 2012). Liver-specific disruption of been ignored in the study of hepatic steatosis because PPARγ or MGAT1 in ob/ob mice improves fatty liver PPARγ expression is low in liver and mainly controls (Matsusue et al. 2003; Lee et al. 2012; Hasenfuss et al. adipogenesis in adipose tissue. However, in human and 2014), strongly suggesting that PPARγ and its regulatory animal models with fatty liver, the hepatic expression of PPARγ and subsequent activation of lipogenic enzymes are pathway is responsible for diet-induced hepatic steatosis. In this case, increased body fat stimulates lipid signaling, significantly up-regulated (Zhang et al. 2006). 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Animal Cells and Systems
– Taylor & Francis
Published: Mar 4, 2014
Keywords: nonalcoholic fatty liver disease; hepatic steatosis; lipid accumulation; PPAR γ; MGAT1