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Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice with metabolic syndrome.
J Hepatol. 2013 Jul; 59(1):144-52.JH

Abstract

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+Show Affiliations

Liver Research Group, ANU Medical School at The Canberra Hospital, Garran, ACT, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23500152

Citation

Van Rooyen, Derrick M., et al. "Pharmacological Cholesterol Lowering Reverses Fibrotic NASH in Obese, Diabetic Mice With Metabolic Syndrome." Journal of Hepatology, vol. 59, no. 1, 2013, pp. 144-52.
Van Rooyen DM, Gan LT, Yeh MM, et al. Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice with metabolic syndrome. J Hepatol. 2013;59(1):144-52.
Van Rooyen, D. M., Gan, L. T., Yeh, M. M., Haigh, W. G., Larter, C. Z., Ioannou, G., Teoh, N. C., & Farrell, G. C. (2013). Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice with metabolic syndrome. Journal of Hepatology, 59(1), 144-52. https://doi.org/10.1016/j.jhep.2013.02.024
Van Rooyen DM, et al. Pharmacological Cholesterol Lowering Reverses Fibrotic NASH in Obese, Diabetic Mice With Metabolic Syndrome. J Hepatol. 2013;59(1):144-52. PubMed PMID: 23500152.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice with metabolic syndrome. AU - Van Rooyen,Derrick M, AU - Gan,Lay T, AU - Yeh,Matthew M, AU - Haigh,W Geoffrey, AU - Larter,Claire Z, AU - Ioannou,George, AU - Teoh,Narci C, AU - Farrell,Geoffrey C, Y1 - 2013/03/07/ PY - 2012/11/06/received PY - 2013/02/10/revised PY - 2013/02/25/accepted PY - 2013/3/19/entrez PY - 2013/3/19/pubmed PY - 2014/2/5/medline SP - 144 EP - 52 JF - Journal of hepatology JO - J. Hepatol. VL - 59 IS - 1 N2 - 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. SN - 1600-0641 UR - https://www.unboundmedicine.com/medline/citation/23500152/Pharmacological_cholesterol_lowering_reverses_fibrotic_NASH_in_obese_diabetic_mice_with_metabolic_syndrome_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-8278(13)00146-3 DB - PRIME DP - Unbound Medicine ER -