title: Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis.
abstract: OBJECTIVE
  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 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.
authors.affiliation: Liver Research Group, ANU Medical School at The Canberra Hospital, Garran, ACT, Australia.
authors.forename: Derrick M
authors.initials: DM
authors.lastname: Van Rooyen
authors.forename: Claire Z
authors.initials: CZ
authors.lastname: Larter
authors.forename: W Geoffrey
authors.initials: WG
authors.lastname: Haigh
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.forename: George
authors.initials: G
authors.lastname: Ioannou
authors.forename: Rahul
authors.initials: R
authors.lastname: Kuver
authors.forename: Sum P
authors.initials: SP
authors.lastname: Lee
authors.forename: Narci C
authors.initials: NC
authors.lastname: Teoh
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Farrell
mesh_terms: D000818:Animals; D017209:Apoptosis; D001647:Bile Acids and Salts / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002791:Cholesterol, Dietary / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D048909:Diabetes Complications / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004951:Esterification; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006868:Hydrolysis; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D009154:Mutation; D065626:Non-alcoholic Fatty Liver Disease; D011973:Receptors, LDL / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D013997:Time Factors
chemical_list: C510001:Alms1 protein, mouse; D001647:Bile Acids and Salts; D018797:Cell Cycle Proteins; D002791:Cholesterol, Dietary; D004268:DNA-Binding Proteins; D007328:Insulin; D011973:Receptors, LDL; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2