Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice with metabolic syndrome

J Hepatol. 2013 Jul;59(1):144-52. doi: 10.1016/j.jhep.2013.02.024. Epub 2013 Mar 7.


Background & aims: We have recently showed that hyperinsulinemia promotes hepatic free cholesterol (FC) accumulation in obese, insulin-resistant Alms1 mutant (foz/foz) mice with NASH. Here we tested whether cholesterol-lowering drugs reduce stress-activated c-Jun N-terminal kinase (JNK) activation, hepatocyte injury/apoptosis, inflammation, and fibrosis in this metabolic syndrome NASH model.

Methods: Female foz/foz and WT mice were fed HF (0.2% cholesterol) 16 weeks, before adding ezetimibe (5 mg/kg), atorvastatin (20 mg/kg), or both to diet, another 8 weeks. Hepatic lipidomic analysis, ALT, liver histology, Sirius Red morphometry, hepatic mRNA and protein expression and immunohistochemistry (IHC) for apoptosis (M30), macrophages (F4/80), and polymorphs (myeloperoxidase) were determined.

Results: In mice with NASH, ezetimibe/atorvastatin combination normalized hepatic FC but did not alter saturated free fatty acids (FFA) and had minimal effects on other lipids; ezetimibe and atorvastatin had similar but less profound effects. Pharmacological lowering of FC abolished JNK activation, improved serum ALT, apoptosis, liver inflammation/NAFLD activity score, designation as "NASH", macrophage chemotactic protein-1 expression, reduced macrophage and polymorph populations, and liver fibrosis.

Conclusions: Cholesterol lowering with ezetimibe/atorvastatin combination reverses hepatic FC but not saturated FFA accumulation. This dampens JNK activation, ALT release, hepatocyte apoptosis, and inflammatory recruitment, with reversal of steatohepatitis pathology and liver fibrosis. Ezetimibe/statin combination is a potent, mechanism-based treatment that could reverse NASH and liver fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin / blood
  • Animals
  • Anticholesteremic Agents / administration & dosage
  • Anticholesteremic Agents / therapeutic use*
  • Atorvastatin
  • Azetidines / administration & dosage
  • Azetidines / therapeutic use
  • Cholesterol / metabolism
  • Diabetes Complications / drug therapy*
  • Diabetes Complications / metabolism
  • Diabetes Complications / pathology
  • Drug Therapy, Combination
  • Ezetimibe
  • Fatty Liver / complications
  • Fatty Liver / drug therapy*
  • Fatty Liver / metabolism
  • Female
  • Heptanoic Acids / administration & dosage
  • Heptanoic Acids / therapeutic use
  • Insulin / blood
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • MAP Kinase Signaling System / drug effects
  • Metabolic Syndrome / complications
  • Metabolic Syndrome / drug therapy*
  • Metabolic Syndrome / metabolism
  • Mice
  • Mice, Mutant Strains
  • Mice, Obese
  • Non-alcoholic Fatty Liver Disease
  • Pyrroles / administration & dosage
  • Pyrroles / therapeutic use


  • Adiponectin
  • Adipoq protein, mouse
  • Anticholesteremic Agents
  • Azetidines
  • Heptanoic Acids
  • Insulin
  • Pyrroles
  • Cholesterol
  • Atorvastatin
  • Ezetimibe