2. Academic Validation
  3. SIK2 regulates fasting-induced PPARα activity and ketogenesis through p300

SIK2 regulates fasting-induced PPARα activity and ketogenesis through p300

  • Sci Rep. 2016 Mar 17;6:23317. doi: 10.1038/srep23317.
Zhen-Ning Zhang 1,  Lulu Gong 2,  Sihan Lv 3,  Jian Li 2,  Xiaolu Tai 2,  Wenqi Cao 2,  Bing Peng 2,  Shen Qu 3,  Weida Li 2,  Chao Zhang 2,  Bing Luan 3
Affiliations

Affiliations

  • 1 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.
  • 2 Translational Medical Center for Stem Cell Therapy &Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • 3 Department of Endocrinology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
PMID: 26983400 DOI: 10.1038/srep23317
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.

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