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“van Rooyen DM, Larter CZ, Decitabine Haigh WG, Yeh MW, Ioannou G, Kuver R, et al. Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis. Gastroenterology 2011;141:1393-1403. (Reprinted with permission.) BACKGROUND & AIMS: Type 2 diabetes and nonalcoholic steatohepatitis

(NASH) are associated with insulin resistance and disordered cholesterol homeostasis. We investigated the basis for hepatic cholesterol accumulation with insulin resistance and its relevance to the pathogenesis of NASH. METHODS: Alms1 mutant (foz/foz) and wild-type NOD.B10 mice were fed high-fat diets that contained varying percentages of cholesterol; hepatic lipid pools and pathways Roxadustat cell line of cholesterol turnover were determined. Hepatocytes were exposed to insulin concentrations that circulate in diabetic foz/foz mice. RESULTS: Hepatic cholesterol accumulation was attributed to up-regulation of low-density lipoprotein receptor via activation of sterol regulatory element binding

protein 2 (SREBP-2), reduced biotransformation to bile acids, and suppression of canalicular pathways for cholesterol and bile acid excretion in bile. Exposing primary hepatocytes to concentrations of insulin that circulate in diabetic Alms1 mice replicated the increases in SREBP-2 and low-density lipoprotein receptor and suppression of bile salt export pump. Removing cholesterol from diet prevented hepatic accumulation of free cholesterol and NASH; increasing dietary cholesterol levels exacerbated hepatic accumulation of free cholesterol, hepatocyte injury or apoptosis, macrophage recruitment, and liver fibrosis. CONCLUSIONS: In obese, diabetic mice, hyperinsulinemia alters nuclear transcriptional regulators of cholesterol homeostasis, leading to hepatic accumulation of free cholesterol; the resulting cytotoxicity mediates transition of steatosis

to NASH. Obesity in the United States and other developed countries is increasing at an alarming rate.1, 2 Among the myriad health complications associated with obesity (including diabetes and cardiovascular risk) is nonalcoholic fatty liver disease (NAFLD). NAFLD is a spectrum of liver diseases ranging from simple Teicoplanin steatosis, to active inflammation (nonalcoholic steatohepatitis [NASH]), to advanced fibrosis and cirrhosis,3 to hepatocellular carcinoma.4 Risk factors for primary NAFLD (i.e., not secondary to other proximate causes) are analogous to those of the metabolic syndrome (e.g., obesity, type II diabetes, and dyslipidemia).5 The prevalence of simple steatosis in individuals at risk for NAFLD can be very high; for example, the prevalence in the severely obese (body mass index >35) has been reported to be 90%.6 In contrast, the prevalence of NASH is much lower in this population (∼40%).6 These factors emphasize that the risk for developing the more severe stages of NAFLD (i.e.