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

被引:93
|
作者
Van Rooyen, Derrick M. [1 ]
Gan, Lay T. [1 ]
Yeh, Matthew M. [2 ]
Haigh, W. Geoffrey [3 ]
Larter, Claire Z. [1 ]
Ioannou, George [3 ]
Teoh, Narci C. [1 ]
Farrell, Geoffrey C. [1 ]
机构
[1] Australian Natl Univ, Sch Med, Liver Res Grp, Canberra Hosp, Garran, ACT 2605, Australia
[2] Univ Washington, Med Ctr, Dept Pathol, Seattle, WA 98195 USA
[3] Univ Washington, Dept Gastroenterol, Seattle, WA 98195 USA
基金
英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;
关键词
Lipotoxicity; Atorvastatin; Ezetimibe; Inflammatory recruitment; Liver fibrosis; FATTY LIVER-DISEASE; NONALCOHOLIC STEATOHEPATITIS; EZETIMIBE; STEATOSIS; EFFICACY; THERAPY; STATINS; ROLES; CELLS; MODEL;
D O I
10.1016/j.jhep.2013.02.024
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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 INK 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 INK 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. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:144 / 152
页数:9
相关论文
共 50 条
  • [1] FREE CHOLESTEROL IS A LIPOTOXIC MEDIATOR IN METABOLIC SYNDROME NASH: LIPIDOMIC ANALYSES, DIETARY AND PHARMACOLIC INTERVENTIONS IN OBESE, DIABETIC MICE
    Van Rooyen, Derrick M.
    Larter, Claire Z.
    Yeh, Matthew M.
    Haigh, Geoff W.
    Teoh, Narci
    Farrell, Geoffrey C.
    [J]. HEPATOLOGY, 2011, 54 : 1154A - 1154A
  • [2] ENDOPLASMIC RETICULUM STRESS DOES NOT CONTRIBUTE TO NASH PATHOGENESIS IN OBESE, DIABETIC MICE WITH METABOLIC SYNDROME
    Legry, V.
    Van Rooyen, D. M.
    Lambert, B. A.
    Sempoux, C.
    Poekes, L.
    Espanol-Suner, R.
    Horsmans, Y.
    Farrell, G. C.
    Leclercq, I. A.
    [J]. JOURNAL OF HEPATOLOGY, 2014, 60 (01) : S149 - S150
  • [3] Disordered hepatic cholesterol turnover in mice with metabolic syndrome: relationship to NASH
    Van Rooyen, D. M.
    Larter, C. Z.
    Teoh, N.
    Farrell, G. C.
    [J]. JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 2009, 24 : A280 - A280
  • [4] PPAR-δ Agonist MBX-8025 Abolishes Lipotoxicity and Reverses NASH in Diabetic Obese Mice
    Haczeyni, Fahrettin
    Wang, Hans
    Barn, Vanessa
    Mridha, Auvro R.
    Yeh, Matthew M.
    Haigh, W. G.
    Ioannou, George N.
    Choi, Yun-Jung
    McWerther, Charles
    Teoh, Narci C.
    Farrell, Geoffrey C.
    [J]. HEPATOLOGY, 2016, 64 : 129A - 129A
  • [5] Cholesterol-lowering gene therapy prevents HFpEF in obese type 2 diabetic mice
    Aboumsallem, J. P.
    Muthuramu, I.
    Mishra, M.
    De Geest, B.
    [J]. EUROPEAN JOURNAL OF HEART FAILURE, 2019, 21 : 165 - 165
  • [6] Cholesterol lowering in patients with CHD and metabolic syndrome
    Butler, Rob
    Wainwright, James
    [J]. LANCET, 2007, 369 (9555): : 27 - 27
  • [7] Dietary cholesterol modulates severity of liver injury in mice with metabolic-syndrome related NASH
    Van Rooyen, D. M.
    Larter, C. Z.
    Yeh, M. M.
    Haigh, W. G.
    Teoh, N.
    Farrell, G. C.
    [J]. JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 2010, 25 : A5 - A6
  • [8] Reversibility of renal injury with cholesterol lowering in hyperlipidemic diabetic mice
    Taneja, Deepa
    Thompson, Joel
    Wilson, Patricia
    Brandewie, Katie
    Schaefer, Liliana
    Mitchell, Bonnie
    Tannock, Lisa R.
    [J]. JOURNAL OF LIPID RESEARCH, 2010, 51 (06) : 1464 - 1470
  • [9] Intervention with citrus flavonoids reverses obesity and improves metabolic syndrome and atherosclerosis in obese Ldlr-/- mice
    Burke, Amy C.
    Sutherland, Brian G.
    Telford, Dawn E.
    Morrow, Marisa R.
    Sawyez, Cynthia G.
    Edwards, Jane Y.
    Drangova, Maria
    Huff, Murray W.
    [J]. JOURNAL OF LIPID RESEARCH, 2018, 59 (09) : 1714 - 1728
  • [10] Cholesterol-Lowering Gene Therapy Prevents Heart Failure with Preserved Ejection Fraction in Obese Type 2 Diabetic Mice
    Aboumsallem, Joseph Pierre
    Muthuramu, Ilayaraja
    Mishra, Mudit
    De Geest, Bart
    [J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2019, 20 (09)