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

Kengo Tomita, Yuichi Oike, Toshiaki Teratani, Takashi Taguchi, Masaaki Noguchi, Takahiro Suzuki, Akiko Mizutani, Hirokazu Yokoyama, Rie Irie, Hidetoshi Sumimoto, Atsushi Takayanagi, Kiichi Miyashita, Masaki Akao, Mitsuhisa Tabata, Gen Tamiya, Tamiko Ohkura, Toshifumi Hibi

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Abstract

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)-α 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)-β1 at all stages of NASH; adiponectin/AdipoR2 signaling ameliorated TGF-β-induced ROS accumulation in primary cultured hepatocytes, by enhancing PPAR-α activity and catalase expression. Conclusion: The adiponectin resistance and sensitivity mediated by AdipoR2 in hepatocytes regulated steatohepatitis progression by changing PPAR-α activity and ROS accumulation, a process in which TGF-β signaling is implicated. Thus, the liver AdipoR2 signaling pathway could be a promising target in treating NASH.

Original languageEnglish
Pages (from-to)458-473
Number of pages16
JournalHepatology
Volume48
Issue number2
DOIs
Publication statusPublished - 2008 Aug 1

ASJC Scopus subject areas

  • Hepatology

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    Tomita, K., Oike, Y., Teratani, T., Taguchi, T., Noguchi, M., Suzuki, T., Mizutani, A., Yokoyama, H., Irie, R., Sumimoto, H., Takayanagi, A., Miyashita, K., Akao, M., Tabata, M., Tamiya, G., Ohkura, T., & Hibi, T. (2008). Hepatic AdipoR2 signaling plays a protective role against progression of nonalcoholic steatohepatitis in mice. Hepatology, 48(2), 458-473. https://doi.org/10.1002/hep.22365