title: Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice with metabolic syndrome.
abstract: OBJECTIVE
  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.
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: Lay T
authors.initials: LT
authors.lastname: Gan
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.forename: W Geoffrey
authors.initials: WG
authors.lastname: Haigh
authors.forename: Claire Z
authors.initials: CZ
authors.lastname: Larter
authors.forename: George
authors.initials: G
authors.lastname: Ioannou
authors.forename: Narci C
authors.initials: NC
authors.lastname: Teoh
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Farrell
mesh_terms: D052242:Adiponectin / Q000097:blood; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000069059:Atorvastatin; D001384:Azetidines / Q000008:administration & dosage / Q000627:therapeutic use; D002784:Cholesterol / Q000378:metabolism; D048909:Diabetes Complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005234:Fatty Liver / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D024821:Metabolic Syndrome / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D000924:Anticholesteremic Agents; D001384:Azetidines; D006538:Heptanoic Acids; D007328:Insulin; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin; D000069438:Ezetimibe