Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis

Gastroenterology. 2011 Oct;141(4):1393-403, 1403.e1-5. doi: 10.1053/j.gastro.2011.06.040. Epub 2011 Jun 23.


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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Bile Acids and Salts / metabolism
  • Cell Cycle Proteins
  • Cells, Cultured
  • Cholesterol, Dietary / metabolism*
  • DNA-Binding Proteins / genetics
  • Diabetes Complications / etiology*
  • Diabetes Complications / genetics
  • Diabetes Complications / metabolism
  • Diabetes Complications / pathology
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Disease Models, Animal
  • Esterification
  • Fatty Liver / etiology*
  • Fatty Liver / genetics
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Female
  • Hepatocytes / metabolism
  • Hydrolysis
  • Insulin / metabolism*
  • Insulin Resistance*
  • Liver / metabolism*
  • Liver / pathology
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / metabolism
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mutation
  • Non-alcoholic Fatty Liver Disease
  • Receptors, LDL / metabolism
  • Sterol Regulatory Element Binding Protein 2 / metabolism
  • Time Factors


  • Alms1 protein, mouse
  • Bile Acids and Salts
  • Cell Cycle Proteins
  • Cholesterol, Dietary
  • DNA-Binding Proteins
  • Insulin
  • Receptors, LDL
  • Srebf2 protein, mouse
  • Sterol Regulatory Element Binding Protein 2