title: Hepatic AdipoR2 signaling plays a protective role against progression of nonalcoholic steatohepatitis in mice.
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)-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)-beta1 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Tomita
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Teratani
authors.forename: Takashi
authors.initials: T
authors.lastname: Taguchi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Noguchi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Akiko
authors.initials: A
authors.lastname: Mizutani
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Yokoyama
authors.forename: Rie
authors.initials: R
authors.lastname: Irie
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Sumimoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takayanagi
authors.forename: Kiichi
authors.initials: K
authors.lastname: Miyashita
authors.forename: Masaki
authors.initials: M
authors.lastname: Akao
authors.forename: Mitsuhisa
authors.initials: M
authors.lastname: Tabata
authors.forename: Gen
authors.initials: G
authors.lastname: Tamiya
authors.forename: Tamiko
authors.initials: T
authors.lastname: Ohkura
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D002796:Choline Deficiency / Q000150:complications; D004032:Diet; D018450:Disease Progression; D004789:Enzyme Activation; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D018014:Gene Transfer Techniques; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D054419:Receptors, Adiponectin / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D047493:PPAR alpha; D017382:Reactive Oxygen Species; D054419:Receptors, Adiponectin; D053773:Transforming Growth Factor beta1; C475421:adiponectin receptor 2, mouse; D008715:Methionine; D002374:Catalase