Rosiglitazone attenuates age- and diet-associated nonalcoholic steatohepatitis in male low-density lipoprotein receptor knockout mice.
Rosiglitazone attenuates age- and diet-associated nonalcoholic steatohepatitis in male low-density lipoprotein receptor knockout mice.
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DOI：
10.1002/hep.23941
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发表时间：
2010-12
期刊：
影响因子：
13.5
通讯作者：
Hsueh, Willa A.
中科院分区：
文献类型：
--
作者：
Gupte, Anisha A.;Liu, Joey Z.;Ren, Yuelan;Minze, Laurie J.;Wiles, Jessica R.;Collins, Alan R.;Lyon, Christopher J.;Pratico, Domenico;Finegold, Milton J.;Wong, Stephen T.;Webb, Paul;Baxter, John D.;Moore, David D.;Hsueh, Willa A.
Nonalcoholic fatty liver disease (NAFLD) is a common complication of obesity that can progress to nonalcoholic steatohepatitis (NASH), a serious liver pathology that can advance to cirrhosis. The mechanisms responsible for NAFLD progression to NASH remain unclear. Lack of a suitable animal model that faithfully recapitulates the pathophysiology of human NASH is a major obstacle in delineating mechanisms responsible for progression of NAFLD to NASH and, thus, development of better treatment strategies. We identified and characterized a novel mouse model, middle-aged male LDLR−/− mice fed high-fat diet (HFD), which developed NASH associated with 4 of 5 metabolic syndrome (MS) components. In MS mice, as observed in humans, liver steatosis and oxidative stress promoted NASH development. Aging exacerbated the HFD-induced NASH such that liver steatosis, inflammation, fibrosis, oxidative stress and liver injury markers were greatly enhanced in middle-aged versus young LDLR−/− mice. While expression of genes mediating fatty acid oxidation and antioxidant responses were upregulated in young LDLR−/− mice fed HFD, they were drastically reduced in MS mice. However, similar to recent human trials, NASH was partially attenuated by an insulin-sensitizing peroxisome proliferator-activated receptor-gamma (PPARγ) ligand, rosiglitazone. In addition to expected improvements in MS, newly identified mechanisms of PPARγ ligand effects included stimulation of antioxidant gene expression and mitochondrial β-oxidation, and suppression of inflammation and fibrosis. LDLR-deficiency promoted NASH, since middle-aged C57BL/6 mice fed HFD did not develop severe inflammation and fibrosis, despite increased steatosis. MS mice represent an ideal model to investigate NASH in the context of MS, as commonly occurs in human disease, and NASH development can be substantially attenuated by PPARγ activation, which enhances β-oxidation.
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DOI：
10.1056/nejmoa0907929
发表时间：
2010-05-06
期刊：
The New England journal of medicine
影响因子：
--
作者：
Sanyal AJ;Chalasani N;Kowdley KV;McCullough A;Diehl AM;Bass NM;Neuschwander-Tetri BA;Lavine JE;Tonascia J;Unalp A;Van Natta M;Clark J;Brunt EM;Kleiner DE;Hoofnagle JH;Robuck PR;NASH CRN
通讯作者：
NASH CRN
影响因子：
13.5
作者：
Ratziu, Vlad;Charlotte, Frederic;Poynard, Thierry
通讯作者：
Poynard, Thierry
影响因子：
7.4
作者：
Debois, Delphine;Bralet, Marie-Pierre;Laprevote, Olivier
通讯作者：
Laprevote, Olivier
影响因子：
14.8
作者：
Frezza, Christian;Cipolat, Sara;Scorrano, Luca
通讯作者：
Scorrano, Luca
影响因子：
25.7
作者：
Rinella, ME;Green, RM
通讯作者：
Green, RM