title: mTORC1 Down-Regulates Cyclin-Dependent Kinase 8 (CDK8) and Cyclin C (CycC).
abstract: In non-alcoholic fatty liver disease (NAFLD) and insulin resistance, hepatic de novo lipogenesis is often elevated, but the underlying mechanisms remain poorly understood. Recently, we show that CDK8 functions to suppress de novo lipogenesis. Here, we identify the mammalian target of rapamycin complex 1 (mTORC1) as a critical regulator of CDK8 and its activating partner CycC. Using pharmacologic and genetic approaches, we show that increased mTORC1 activation causes the reduction of the CDK8-CycC complex in vitro and in mouse liver in vivo. In addition, mTORC1 is more active in three mouse models of NAFLD, correlated with the lower abundance of the CDK8-CycC complex. Consistent with the inhibitory role of CDK8 on de novo lipogenesis, nuclear SREBP-1c proteins and lipogenic enzymes are accumulated in NAFLD models. Thus, our results suggest that mTORC1 activation in NAFLD and insulin resistance results in down-regulation of the CDK8-CycC complex and elevation of lipogenic protein expression.
authors.affiliation: Division of Endocrinology, Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, New York, New York, United States of America.
authors.forename: Daorong
authors.initials: D
authors.lastname: Feng
authors.affiliation: Division of Endocrinology, Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, New York, New York, United States of America.
authors.forename: Dou Yeon
authors.initials: DY
authors.lastname: Youn
authors.affiliation: Division of Endocrinology, Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, New York, New York, United States of America; Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Division of Endocrinology, Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, New York, New York, United States of America; School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Yanguang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: William J
authors.initials: WJ
authors.lastname: Quinn
authors.affiliation: Division of Endocrinology, Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, New York, New York, United States of America.
authors.forename: Alus M
authors.initials: AM
authors.lastname: Xiaoli
authors.affiliation: Department of Geriatrics, Zhongshan Hospital of Fudan University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.affiliation: Division of Endocrinology, Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, New York, New York, United States of America; Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, New York, United States of America.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Pessin
authors.affiliation: Division of Endocrinology, Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, New York, New York, United States of America; Department of Developmental & Molecular Biology, Albert Einstein College of Medicine, New York, New York, United States of America.
authors.forename: Fajun
authors.initials: F
authors.lastname: Yang
mesh_terms: D000818:Animals; D056745:Cyclin C / Q000096:biosynthesis* / Q000235:genetics; D056850:Cyclin-Dependent Kinase 8 / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D050155:Lipogenesis / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C503674:CCNC protein, human; C503675:Ccnc protein, mouse; D056745:Cyclin C; D046912:Multiprotein Complexes; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C095686:CDK8 protein, human; C524803:Cdk8 protein, mouse; D056850:Cyclin-Dependent Kinase 8