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

研究成果: Article

95 引用 (Scopus)

抄録

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.

元の言語English
ページ(範囲)458-473
ページ数16
ジャーナルHepatology
48
発行部数2
DOI
出版物ステータスPublished - 2008 8

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Liver
Peroxisome Proliferator-Activated Receptors
Adiponectin
Transforming Growth Factors
Reactive Oxygen Species
Adenoviridae
Catalase
Hepatocytes
Fibrosis
Non-alcoholic Fatty Liver Disease
Adiponectin Receptors
Acyl-CoA Oxidase
Fatty Liver
Choline
Inbred C57BL Mouse
Methionine
Small Interfering RNA
Lipid Peroxidation
Animal Models
Pathology

ASJC Scopus subject areas

  • Hepatology

これを引用

Tomita, K., Oike, Y., Teratani, T., Taguchi, T., Noguchi, M., Suzuki, 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

Hepatic AdipoR2 signaling plays a protective role against progression of nonalcoholic steatohepatitis in mice. / Tomita, Kengo; Oike, Yuichi; Teratani, Toshiaki; Taguchi, Takashi; Noguchi, Masaaki; Suzuki, Takahiro; Mizutani, Akiko; Yokoyama, Hirokazu; Irie, Rie; Sumimoto, Hidetoshi; Takayanagi, Atsushi; Miyashita, Kiichi; Akao, Masaki; Tabata, Mitsuhisa; Tamiya, Gen; Ohkura, Tamiko; Hibi, Toshifumi.

:: Hepatology, 巻 48, 番号 2, 08.2008, p. 458-473.

研究成果: Article

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, 巻. 48, 番号 2, pp. 458-473. https://doi.org/10.1002/hep.22365
Tomita, Kengo ; Oike, Yuichi ; Teratani, Toshiaki ; Taguchi, Takashi ; Noguchi, Masaaki ; Suzuki, Takahiro ; Mizutani, Akiko ; Yokoyama, Hirokazu ; Irie, Rie ; Sumimoto, Hidetoshi ; Takayanagi, Atsushi ; Miyashita, Kiichi ; Akao, Masaki ; Tabata, Mitsuhisa ; Tamiya, Gen ; Ohkura, Tamiko ; Hibi, Toshifumi. / Hepatic AdipoR2 signaling plays a protective role against progression of nonalcoholic steatohepatitis in mice. :: Hepatology. 2008 ; 巻 48, 番号 2. pp. 458-473.
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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.",
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AU - Noguchi, Masaaki

AU - Suzuki, Takahiro

AU - Mizutani, Akiko

AU - Yokoyama, Hirokazu

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AU - Sumimoto, Hidetoshi

AU - Takayanagi, Atsushi

AU - Miyashita, Kiichi

AU - Akao, Masaki

AU - Tabata, Mitsuhisa

AU - Tamiya, Gen

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AU - Hibi, Toshifumi

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