title: Activation of ERK1/2 Ameliorates Liver Steatosis in Leptin Receptor-Deficient (db/db) Mice via Stimulating ATG7-Dependent Autophagy.
abstract: Although numerous functions of extracellular signal-regulated kinase 1/2 (ERK1/2) are identified, a direct effect of ERK1/2 on liver steatosis has not been reported. Here, we show that ERK1/2 activity is compromised in livers of leptin receptor-deficient (db/db) mice. Adenovirus-mediated activation of mitogen-activated protein kinase kinase 1 (MEK1), the upstream regulator of ERK1/2, significantly ameliorated liver steatosis in db/db mice, increased expression of genes related to fatty acid β-oxidation and triglyceride (TG) export and increased serum β-hydroxybutyrate (3-HB) levels. Opposite effects were observed in adenovirus-mediated ERK1/2 knockdown C57/B6J wild-type mice. Furthermore, autophagy and autophagy-related protein 7 (ATG7) expression were decreased or increased by ERK1/2 knockdown or activation, respectively, in primary hepatocytes and liver. Blockade of autophagy by the autophagy inhibitor chloroquine or adenovirus-mediated ATG7 knockdown reversed the ameliorated liver steatosis in recombinant adenoviruses construct expressing rat constitutively active MEK1 Ad-CA MEK1 db/db mice, decreased expression of genes related to fatty acid β-oxidation and TG export, and decreased serum 3-HB levels. Finally, ERK1/2 regulated ATG7 expression in a p38-dependent pathway. Taken together, these results identify a novel beneficial role for ERK1/2 in liver steatosis via promoting ATG7-dependent autophagy, which provides new insights into the mechanisms underlying liver steatosis and important hints for targeting ERK1/2 in treating liver steatosis.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Graduate School of the Chinese Academy of Sciences, The Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Graduate School of the Chinese Academy of Sciences, The Chinese Academy of Sciences, Shanghai, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Graduate School of the Chinese Academy of Sciences, The Chinese Academy of Sciences, Shanghai, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Yu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Graduate School of the Chinese Academy of Sciences, The Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zilong
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Graduate School of the Chinese Academy of Sciences, The Chinese Academy of Sciences, Shanghai, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Graduate School of the Chinese Academy of Sciences, The Chinese Academy of Sciences, Shanghai, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Xia
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Graduate School of the Chinese Academy of Sciences, The Chinese Academy of Sciences, Shanghai, China.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Graduate School of the Chinese Academy of Sciences, The Chinese Academy of Sciences, Shanghai, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Graduate School of the Chinese Academy of Sciences, The Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Deng
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Graduate School of the Chinese Academy of Sciences, The Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Graduate School of the Chinese Academy of Sciences, The Chinese Academy of Sciences, Shanghai, China.
authors.forename: Shanghai
authors.initials: S
authors.lastname: Chen
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Graduate School of the Chinese Academy of Sciences, The Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Graduate School of the Chinese Academy of Sciences, The Chinese Academy of Sciences, Shanghai, China ffguo@sibs.ac.cn.
authors.forename: Feifan
authors.initials: F
authors.lastname: Guo
mesh_terms: D020155:3-Hydroxybutyric Acid; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D004789:Enzyme Activation; D005234:Fatty Liver / Q000201:enzymology* / Q000209:etiology; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D054411:Receptors, Leptin / Q000172:deficiency*; D014280:Triglycerides / Q000378:metabolism
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D054411:Receptors, Leptin; D014280:Triglycerides; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D000071193:Autophagy-Related Protein 7; D020155:3-Hydroxybutyric Acid