nonalcoholic fatty liver disease ( nafld ) is a medical condition characterized by the accumulation of fat in the liver . nafld is used to describe a range of states from simple accumulation of triglycerides ( tg ) in hepatocytes to the condition with inflammation , fibrosis , and cirrhosis . the prevalence of nafld has been reported in the range of 10% to 24% of normal and 58% to 74% of obese people , depending on the population studied and the analytic methods used . the simple accumulation of tg in hepatocytes is not considered a serious disease condition and is often self - limited ; however , 4% to 27% of the patients with severe fatty liver that is not treated properly could develop cirrhosis , which can ultimately develop into hepatocellular carcinoma . various drugs , hormones , and multiple genetic defects in energy metabolism can cause fat accumulation in the liver . however , the most common cause of nafld is insulin resistance , which is closely related with obesity , diabetes , and dyslipidemia . changing lifestyles including weight loss , diet , and exercise to control the related conditions such as obesity and diabetes is the treatment of choice for fatty liver diseases . drugs that improve insulin resistance and dyslipidemia , antioxidants , and bile acids are currently used for treatments , but the effects are limited , and some of the drugs often produce serious side effects . this review will discuss molecular changes that mediate hepatic tg accumulation in insulin resistance and focus on recent animal studies that suggest a new therapeutic target for hepatic steatosis and hypertriglyceridemia . the fatty acids for hepatic tg are derived from three sources : ( 1 ) dietary fat , ( 2 ) free fatty acids released from adipose tissue , and ( 3 ) hepatic de novo lipogenesis . a series of metabolic alterations occur in the liver in insulin - resistant states . in normal people , 80% of hepatic fatty acids are derived from adipose tissue , while those from de novo lipogenesis and diet account for 5% and 15% , respectively . however , in obese and hyperinsulinemic nafld patients , the portion from de novo lipogenesis is increased to 26% . in livers of rodent models of insulin resistance , increased rates of fatty acid synthesis are a significant contributor of the development of hepatic steatosis . in the setting of increased lipogenesis , mitochondrial fatty acid oxidation is reduced . in adipocytes , hormone - sensitive lipase activity is increased in insulin resistance , which results in continuous release of free fatty acid through tg lipolysis . therefore , in an insulin - resistant state , the increased influx of fatty acids from adipocytes , increased de novo lipogenesis , and reduced fatty acid oxidation result in tg accumulation in the liver ( fig . hepatic de novo lipogenesis is mainly regulated by transcriptional control of the genes involved in the process by transcription factors such as sterol regulatory element binding protein-1c ( srebp-1c ) , carbohydrate response element binding protein ( chrebp ) , liver x receptor  , and peroxisome proliferator - activated receptor  . among these , srebp-1c is the main transcription factor that regulates hepatic de novo lipogenesis by insulin . srebp-1c is one of three srebp isoforms ( srebp-1a , srebp-1c , and srebp-2 ) that belong to the basic helix - loop - helix - leucine zipper family of transcription factors . srebp-1a and 1c are derived from a single gene using different promoters and exon 1s . the longer acidic nh2-terminus of srebp-1a makes it more potent than srebp-1c and can activate all srebp - responsive genes that mediate the synthesis of fatty acids , tg , and cholesterol . srebp-1c preferentially enhances transcription of genes required for fatty acid synthesis , while srebp-2 preferentially activates genes required for cholesterol synthesis . srebp-1c and srebp-2 are predominant isoforms in the liver and most other intact tissues , and srebp-1c is regulated by insulin . srebps are synthesized as inactive precursors that are bound to the endoplasmic reticulum ( er ) membrane through two hydrophobic transmembrane - spanning segments connected by a short loop . the nh2-terminal domain of srebp is the transcription factor region that must be released proteolytically by the two proteases on golgi apparatus . srebp cleavage activating protein ( scap ) is required in this process by escorting srebp from the er to the golgi as well as by sensing sterol level in the cell . other players in the srebp process are insigs ( insulin induced genes ) , which are associated with scap . dissociation of insigs from the scap - srebp complex is required for the srebp - scap complex to move to the golgi . the released nh2-terminal domain enters the nucleus where it activates multiple target genes by binding to the sres ( sterol response elements ) in their promoter ( fig . enzymes that catalyze the synthesis of fatty acids , tg , and nadph required for fatty acid synthesis are regulated by srebp-1c . the typical genes regulated by srebp-1c are atp - citrate lyase , acetyl - coenzyme a ( coa ) carboxylase , fatty acid synthase , elovl6 ( elongation of long chain fatty acids family member 6 ) , stearoyl - coa desaturase , glycerol-3-phosphate acyl transferase , malic enzyme , and glucose 6-phosphate dehydrogenase . the in vivo role of srebp-1c was demonstrated in a transgenic mouse model that overexpresses srebp-1c in the liver , which leads to the development of hepatic steatosis due to the increase in lipogenesis . increased rates of hepatic fatty acid synthesis contribute to the development of hepatic steatosis in rodent models of insulin - resistance and obesity . the leptin - deficient ob / ob mouse is a model of insulin resistance and severe obesity that is commonly used in metabolic studies . hyperglycemia , hyperinsulinemia , and hyperphagia along with insulin resistance and severe obesity are the representative characteristics of this model . hyperinsulinemia in ob / ob mice leads to hepatic srebp-1c activation and hepatic steatosis , while hepatic glucose production is increased due to insulin resistance . the deletion of the srebp-1c gene in the liver of ob / ob mice results in an approximately 50% reduction of hepatic tg , which indicates a significant role of srebp-1c in the hepatic steatosis exhibited in the ob / ob mouse , a model of insulin resistance . compensatory activation of srebp-2 in the absence of srebp-1c and the activation of chrebp by high glucose level are expected for the residual elevation of tg in the liver of this model . it activates liver pyruvate kinase , which generates pyruvate , a source of acetyl - coa , from phosphoenolpyruvate , as well as genes involved in fatty acid synthesis . disruption of scap in the liver precludes proteolytic cleavage of the nh2-terminal region of srebps and abolishes the nuclear forms of all srebp-1 and -2 in the liver . when scap is deleted in the liver of normal mouse lines ( l - scap ) , the expression of target genes in both the cholesterol and the fatty acid synthetic pathways are reduced , and the rates of fatty acid and cholesterol synthesis are diminished by 70% to 80% in the liver . in ob / ob mice , the mrnas of the genes involved in fatty acid synthesis are markedly elevated because of the srebp-1c activation . the scap deletion in the liver of ob / ob mice ( l - scap ; ob / ob ) abolishes this elevation of lipogenic gene expression , which results in a 90% reduction in fatty acid synthesis rate . the large pale livers in ob / ob mice caused by the massive engorgement with tg are restored to a normal shape . in fact , the hepatic tg contents are completely resolved to normal or even lower than normal levels . the same effects are observed in the insulin resistance model induced by long - term feeding of a high - fat diet . despite the abolishment of hepatic steatosis in l - scap ; ob / ob mice , the plasma insulin and plasma glucose levels remain high . they fail to improve intolerance to glucose or insulin challenges shown in ob / ob mice with hepatic steatosis . l - scap ; ob / ob mice are one example showing that hepatic fatty acid overproduction is not required for the development of systemic insulin resistance in mice , and hepatic steatosis and insulin resistance may be independent conditions . in humans , evidence has shown that nafld is an independent risk factor of atherogenic dyslipidemia in various clinical studies . hamsters easily develop insulin resistance and dyslipidemia after several weeks of being fed a high - fructose diet . as compared with mice , the hamster lipoprotein metabolism more closely resembles that of humans , and high - fructose diets raise plasma very low density lipoprotein ( vldl)-tg and cholesterol levels as well as hepatic tg content . a high - sucrose diet induces hepatic srebp-1 and the mrna levels of the genes required for fatty acid synthesis such as acetyl - coa carboxylase and fatty acid synthase . depletion of scap mrna by rnai in hamsters fed a high - sucrose diet for several weeks diminishes scap protein in the liver and nuclear srebps , which results in the normalization of mrna levels of those genes . the inhibition of srebp-1c activation by scap rnai can normalize hepatic tg content as well as plasma vldl - tg and vldl - cholesterol in hamsters . the secretion rates of vldl - tg are reduced by 40% ; however , scap - rnai does not significantly affect body weight , plasma insulin level , or blood glucose level in hamsters . in an insulin - resistant state , the increased influx of fatty acids from adipocytes , the increase in de novo lipogenesis , and reduced fatty acid oxidation result in tg accumulation in the liver . activation of srebp-1c , the main transcription factor that increases hepatic fatty acid and tg synthesis , is presented in insulin resistance . inhibition of scap prevents the activation of srebps and the expression of genes required for fatty acid and tg synthesis , which results in the inhibition of de novo fatty acid synthesis . as a consequence , the inhibition of scap can resolve hepatic steatosis and hypertriglyceridemia in animal models of insulin resistance . further human studies will reveal whether inhibition of scap has the same therapeutic effects in humans as it does in animal models .
nonalcoholic fatty liver disease ( nafld ) is strongly associated with insulin resistance , obesity , and dyslipidemia . 
 nafld encompasses a wide range of states from the simple accumulation of triglycerides in the hepatocytes to serious states accompanied by inflammation and fibrosis in the liver . 
 de novo lipogenesis has been shown to be a significant factor in the development of hepatic steatosis in insulin - resistant states . 
 sterol regulatory element binding protein-1c ( srebp-1c ) is the main transcription factor that mediates the activation of lipogenesis , and srebp cleavage activating protein ( scap ) is required for the activation of srebps . here , 
 recent animal studies that suggest scap as a therapeutic target for hepatic steatosis and hypertriglyceridemia are discussed .