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.
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.
Authors: George N Ioannou; Savitha Subramanian; Alan Chait; W Geoffrey Haigh; Matthew M Yeh; Geoffrey C Farrell; Sum P Lee; Christopher Savard Journal: J Lipid Res Date: 2017-04-12 Impact factor: 5.922
Authors: Wen Liang; Jan H Lindeman; Aswin L Menke; Debby P Koonen; Martine Morrison; Louis M Havekes; Anita M van den Hoek; Robert Kleemann Journal: Lab Invest Date: 2014-02-24 Impact factor: 5.662