title: SIK2 regulates fasting-induced PPARα activity and ketogenesis through p300.
abstract: Fatty acid oxidation and subsequent ketogenesis is one of the major mechanisms to maintain hepatic lipid homeostasis under fasting conditions. Fasting hormone glucagon has been shown to stimulate ketone body production through activation of PPARα; however, the signal pathway linking glucagon to PPARα is largely undiscovered. Here we report that a SIK2-p300-PPARα cascade mediates glucagon's effect on ketogenesis. p300 interacts with PPARα through a conserved LXXLL motif and enhances its transcriptional activity. SIK2 disrupts p300-PPARα interaction by direct phosphorylation of p300 at Ser89, which in turn decreases PPARα-mediated ketogenic gene expression. Moreover, SIK2 phosphorylation defective p300 (p300 S89A) shows increased interaction with PPARα and abolishes suppression of SIK2 on PPARα-mediated ketogenic gene expression in liver. Taken together, our results unveil the signal pathway that mediates fasting induced ketogenesis to maintain hepatic lipid homeostasis.
authors.affiliation: Department of Endocrinology, Shanghai Tenth People's Hospital; Translational Medical Center for Stem Cell Therapy &Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University, Shanghai, China.
authors.forename: Zhen-Ning
authors.initials: ZN
authors.lastname: Zhang
authors.affiliation: Translational Medical Center for Stem Cell Therapy &Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Gong
authors.affiliation: Department of Endocrinology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
authors.forename: Sihan
authors.initials: S
authors.lastname: Lv
authors.affiliation: Translational Medical Center for Stem Cell Therapy &Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Translational Medical Center for Stem Cell Therapy &Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Tai
authors.affiliation: Translational Medical Center for Stem Cell Therapy &Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Cao
authors.affiliation: Translational Medical Center for Stem Cell Therapy &Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Peng
authors.affiliation: Department of Endocrinology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Qu
authors.affiliation: Translational Medical Center for Stem Cell Therapy &Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
authors.forename: Weida
authors.initials: W
authors.lastname: Li
authors.affiliation: Translational Medical Center for Stem Cell Therapy &Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Luan
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D050881:E1A-Associated p300 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005215:Fasting; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006801:Humans; D015151:Immunoblotting; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D047493:PPAR alpha; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; C474808:salt-inducible kinase-2, mouse; D017346:Protein Serine-Threonine Kinases