Hepatic AdipoR2 signaling plays a protective role against progression of nonalcoholic steatohepatitis in mice

被引：102

作者：

Tomita, Kengo

Oike, Yuichi ^{[2
]}

Teratani, Toshiaki

Taguchi, Takashi

Noguchi, Masaaki ^{[3
]}

Suzuki, Takahiro

Mizutani, Akiko ^{[4
]}

Yokoyama, Hirokazu ^{[5
]}

Irie, Rie ^{[6
]}

Sumimoto, Hidetoshi ^{[3
]}

Takayanagi, Atsushi ^{[7
]}

Miyashita, Kiichi ^{[8
]}

Akao, Masaki ^{[9
]}

Tabata, Mitsuhisa ^{[2
]}

Tamiya, Gen ^{[10
]}

Ohkura, Tamiko ^{[3
]}

Hibi, Toshifumi ^{[1
]}

机构：

[1] Keio Univ, Sch Med, Dept Internal Med, Div Gastroenterol & Hepatol,Shinjuku Ku, Tokyo 1608582, Japan

[2] Kumamoto Univ, Dept Mol Genet, Grad Sch Med Sci, Kumamoto, Japan

[3] Keio Univ, Sch Med, Inst Adv Med Res, Tokyo 1608582, Japan

[4] Tokai Univ, Sch Med, Dept Mol Life Sci, Kanagawa 2591100, Japan

[5] Keio Univ, Sch Med, Ctr Hlth, Tokyo 1608582, Japan

[6] Keio Univ, Sch Med, Dept Diagnost Pathol, Tokyo 1608582, Japan

[7] Keio Univ, Sch Med, Dept Mol Biol, Tokyo 1608582, Japan

[8] Keio Univ, Sch Med, Cent Res Lab, Tokyo 1608582, Japan

[9] Keio Univ, Sch Med, Dept Cell Differentiat, Tokyo 1608582, Japan

[10] Univ Tokushima, Grad Sch Med, Dept Neurol, Tokushima 770, Japan

来源：

HEPATOLOGY | 2008年 / 48卷 / 02期

关键词：

D O I：

10.1002/hep.22365

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

It is unclear how hepatic adiponectin resistance and sensitivity mediated by the adiponectin receptor, AdipoR2, contributes to the progression of nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the roles of hepatic AdipoR2 in NASH, using an animal model. We fed C57BL/6 mice a methionine-deficient and choline-deficient (MCD) diet for up to 8 weeks and analyzed changes in liver pathology caused by either an AdipoR2 short hairpin RNA-expressing adenovirus or an AdipoR2-overexpressing adenovirus. Inhibition of hepatic AdipoR2 expression aggravated the pathological state of NASH at all stages: fatty changes, inflammation, and fibrosis. In contrast, enhancement of AdipoR2 expression in the liver improved NASH at every stage, from the early stage to the progression of fibrosis. Inhibition of AdipoR2 signaling in the liver diminished hepatic peroxisome proliferator activated receptor (PPAR)-alpha signaling, with decreased expression of acyl-CoA oxidase (ACO) and catalase, leading to an increase in lipid peroxidation. Hepatic AdipoR2 overexpression had the opposite effect. Reactive oxygen species (ROS) accumulation in liver increases hepatic production of transforming growth factor (TGF)-beta 1 at all stages of NASH; adiponectin/AdipoR2 signaling ameliorated TGF-beta-induced ROS accumulation in primary cultured hepatocytes, by enhancing PPAR-alpha activity and catalase expression. Conclusion: The adiponectin resistance and sensitivity mediated by AdipoR2 in hepatocytes regulated steatohepatitis progression by changing PPAR-alpha activity and ROS accumulation, a process in which TGF-beta signaling is implicated. Thus, the liver AdipoR2 signaling pathway could be a promising target in treating NASH.

引用

页码：458 / 473

页数：16

共 27 条

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