title: PIASy-mediated sumoylation of SREBP1c regulates hepatic lipid metabolism upon fasting signaling.
abstract: SREBP1c is a key transcription factor that regulates de novo lipogenesis during anabolic periods. However, the molecular mechanisms involved in the suppression of SREBP1c under nutritional deprivation are largely unknown. In this study, we demonstrate that the small ubiquitin-related modifier (SUMO) E3 ligase, a protein inhibitor of activated STAT Y (PIASy), sumoylates SREBP1c at Lys98, leading to suppression of the hepatic lipogenic program upon fasting-induced signals. In primary hepatocytes, ablation of PIASy stimulated intracellular lipid accumulation through the induction of SREBP1c and its target genes. Given that protein kinase A (PKA) plays important roles in catabolic responses, activated PKA enhances the sumoylation of SREBP1c and potentiates the interaction between SREBP1c and PIASy. Notably, overexpression of PIASy in obese db/db mice ameliorated hepatic steatosis, while suppression of PIASy in lean (wild-type) mice stimulated hepatic lipogenesis with increased expression of SREBP1c target genes. Furthermore, PKA-mediated SREBP1c phosphorylation augmented SREBP1c sumoylation, subsequently leading to degradation of SREBP1c via ubiquitination. Together, these data suggest that PKA-induced SREBP1c sumoylation by PIASy is a key regulatory mechanism to turn off hepatic lipogenesis during nutritional deprivation.
authors.affiliation: National Creative Research Initiatives Center for Adipose Tissue Remodeling, Seoul National University, Seoul, South Korea.
authors.forename: Gha Young
authors.initials: GY
authors.lastname: Lee
authors.forename: Hagoon
authors.initials: H
authors.lastname: Jang
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Huh
authors.forename: Sekyu
authors.initials: S
authors.lastname: Choi
authors.forename: Jongkyeong
authors.initials: J
authors.lastname: Chung
authors.forename: Jae Bum
authors.initials: JB
authors.lastname: Kim
mesh_terms: D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D005215:Fasting / Q000378:metabolism* / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D050155:Lipogenesis / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics / Q000502:physiology
chemical_list: C414349:Piasy protein, mouse; D050828:Protein Inhibitors of Activated STAT; D025842:SUMO-1 Protein; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D044767:Ubiquitin-Protein Ligases; D017868:Cyclic AMP-Dependent Protein Kinases