title: CHIP(-/-)-Mouse Liver: Adiponectin-AMPK-FOXO-Activation Overrides CYP2E1-Elicited JNK1-Activation, Delaying Onset of NASH: Therapeutic Implications.
abstract: Genetic ablation of C-terminus of Hsc70-interacting protein (CHIP) E3 ubiquitin-ligase impairs hepatic cytochrome P450 CYP2E1 degradation. Consequent CYP2E1 gain of function accelerates reactive O2 species (ROS) production, triggering oxidative/proteotoxic stress associated with sustained activation of c-Jun NH2-terminal kinase (JNK)-signaling cascades, pro-inflammatory effectors/cytokines, insulin resistance, progressive hepatocellular ballooning and microvesicular steatosis. Despite this, little evidence of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) was found in CHIP(-/-)-mice over the first 8-9-months of life. We herein document that this lack of tissue injury is largely due to the concurrent up-regulation and/or activation of the adiponectin-5'-AMP-activated protein kinase (AMPK)-forkhead box O (FOXO)-signaling axis stemming from at the least three synergistic features: Up-regulated expression of adipose tissue adiponectin and its hepatic adipoR1/adipoR2 receptors, stabilization of hepatic AMPKα1-isoform, identified herein for the first time as a CHIP-ubiquitination substrate (unlike its AMPKα2-isoform), as well as nuclear stabilization of FOXOs, well-known CHIP-ubiquitination targets. Such beneficial predominance of the adiponectin-AMPK-FOXO-signaling axis over the sustained JNK-elevation and injurious insulin resistance in CHIP(-/-)-livers apparently counteracts/delays rapid progression of the hepatic microvesicular steatosis to the characteristic macrovesicular steatosis observed in clinical NASH and/or rodent NASH-models.
authors.affiliation: Department of Cellular &Molecular Pharmacology, University of California San Francisco, San Francisco CA 94158-2517, USA.
authors.forename: Sung-Mi
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco CA 94158-2517, USA.|The Liver Center, University of California San Francisco, San Francisco CA 94158-2517, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Grenert
authors.affiliation: Department of Medicine, Presbyterian Hospital/Weill-Cornell Medical Center, New York, NY 10065, USA.
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.affiliation: Department of Cellular &Molecular Pharmacology, University of California San Francisco, San Francisco CA 94158-2517, USA.|The Liver Center, University of California San Francisco, San Francisco CA 94158-2517, USA.|Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco CA 94158-2517, USA.|Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco CA 94158-2517, USA.
authors.forename: Maria Almira
authors.initials: MA
authors.lastname: Correia
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000473:pathology*; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D054419:Receptors, Adiponectin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D054875:Ubiquitination / Q000502:physiology
chemical_list: D052242:Adiponectin; D051858:Forkhead Transcription Factors; D017382:Reactive Oxygen Species; D054419:Receptors, Adiponectin; C475419:adiponectin receptor 1, mouse; C475421:adiponectin receptor 2, mouse; D019392:Cytochrome P-450 CYP2E1; C000617651:cytochrome P-450 2E1, mouse; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C548179:Prkaa1 protein, mouse; D048055:Mitogen-Activated Protein Kinase 8; D055372:AMP-Activated Protein Kinases