title: Transcriptional activation of lipogenesis by insulin requires phosphorylation of MED17 by CK2.
abstract: De novo lipogenesis is precisely regulated by nutritional and hormonal conditions. The genes encoding various enzymes involved in this process, such as fatty acid synthase (FASN), are transcriptionally activated in response to insulin. We showed that USF1, a key transcription factor forFASNactivation, directly interacted with the Mediator subunit MED17 at theFASNpromoter. This interaction recruited Mediator, which can bring POL II and other general transcription machinery to the complex. Moreover, we showed that MED17 was phosphorylated at Ser53by casein kinase 2 (CK2) in the livers of fed mice or insulin-stimulated hepatocytes, but not in the livers of fasted mice or untreated hepatocytes. Furthermore, activation of theFASNpromoter in response to insulin required this CK2-mediated phosphorylation event, which occurred only in the absence of p38 MAPK-mediated phosphorylation at Thr570Overexpression of a nonphosphorylatable S53A MED17 mutant or knockdown of MED17, as well as CK2 knockdown or inhibition, impaired hepatic de novo fatty acid synthesis and decreased triglyceride content in mice. These results demonstrate that CK2-mediated phosphorylation of Ser53in MED17 is required for the transcriptional activation of lipogenic genes in response to insulin.
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Jose A
authors.identifier: 0000-0003-1273-4098
authors.initials: JA
authors.lastname: Viscarra
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Il-Hwa
authors.initials: IH
authors.lastname: Hong
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA. hsul@berkeley.edu.
authors.forename: Hei Sook
authors.identifier: 0000-0002-3372-5097
authors.initials: HS
authors.lastname: Sul
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism*; D054890:Fatty Acid Synthase, Type I / Q000378:metabolism; D005227:Fatty Acids / Q000097:blood / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D050155:Lipogenesis; D008297:Male; D056892:Mediator Complex / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D020125:Mutation, Missense; D010766:Phosphorylation; D015533:Transcriptional Activation
chemical_list: D005227:Fatty Acids; D007328:Insulin; D056892:Mediator Complex; D054890:Fatty Acid Synthase, Type I; D047390:Casein Kinase II