title: C1q/TNF-Related Protein 9 (CTRP9) attenuates hepatic steatosis via the autophagy-mediated inhibition of endoplasmic reticulum stress.
abstract: C1q/TNF-Related Protein (CTRP) 9, the closest paralog of adiponectin, has been reported to protect against diet-induced obesity and non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism has not been fully elucidated. We explored the protective effect of CTRP9 against hepatic steatosis and apoptosis, and identified the mechanisms through autophagy and endoplasmic reticulum (ER) stress using in vitro and in vivo experiments. Treating HepG2 cells with human recombinant CTRP9 significantly ameliorated palmitate- or tunicamycin-induced dysregulation of lipid metabolism, caspase 3 activity and chromatin condensation, which lead to reduction of hepatic triglyceride (TG) accumulation. CTRP9 treatment induced autophagy markers including LC3 conversion, P62 degradation, Beclin1 and ATG7 through AMPK phosphorylation in human primary hepatocytes. Furthermore, CTRP9 decreased palmitate- or tunicamycin-induced ER stress markers, such as eIF2α, CHOP and IRE-1, in HepG2 cells. Compound C, an AMPK inhibitor, and 3 methyladenine (3 MA), an autophagy inhibitor, canceled the effects of CTRP9 on ER stress, apoptosis and hepatic steatosis. In the livers of HFD-fed mice, adenovirus-mediated CTRP9 overexpression significantly induced AMPK phosphorylation and autophagy, whereas suppressed ER stress markers. In addition, both SREBP1-mediated lipogenic gene expression and apoptosis were significantly attenuated, which result in improvement in hepatic steatosis by overexpression of CTRP9. These results demonstrate that CTRP9 alleviates hepatic steatosis through relief of ER stress via the AMPK-mediated induction of autophagy.
authors.affiliation: The Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Jung
authors.affiliation: The Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Ho Cheol
authors.initials: HC
authors.lastname: Hong
authors.affiliation: The Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Hwan-Jin
authors.initials: HJ
authors.lastname: Hwang
authors.affiliation: The Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Yoo
authors.affiliation: The Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Sei Hyun
authors.initials: SH
authors.lastname: Baik
authors.affiliation: The Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea. Electronic address: medica7@gmail.com.
authors.forename: Kyung Mook
authors.initials: KM
authors.lastname: Choi
mesh_terms: D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D019308:Palmitic Acid / Q000494:pharmacology; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D052242:Adiponectin; C543615:C1QTNF9B protein, human; C534692:CTRP9 protein, mouse; D006023:Glycoproteins; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014415:Tunicamycin; D019308:Palmitic Acid
keywords: AMP-activated protein kinase; Apoptosis; Autophagy; C1q/TNF-Related Protein 9; Endoplasmic reticulum stress; Non-alcoholic fatty liver