SIK2 regulates fasting-induced PPAR? 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 PPAR?; however, the signal pathway linking glucagon to PPAR? is largely undiscovered. Here we report that a SIK2-p300-PPAR? cascade mediates glucagon's effect on ketogenesis. p300 interacts with PPAR? through a conserved LXXLL motif and enhances its transcriptional activity. SIK2 disrupts p300-PPAR? interaction by direct phosphorylation of p300 at Ser89, which in turn decreases PPAR?-mediated ketogenic gene expression. Moreover, SIK2 phosphorylation defective p300 (p300 S89A) shows increased interaction with PPAR? and abolishes suppression of SIK2 on PPAR?-mediated ketogenic gene expression in liver. Taken together, our results unveil the signal pathway that mediates fasting induced ketogenesis to maintain hepatic lipid homeostasis.

SUBMITTER: Zhang ZN 

PROVIDER: S-EPMC4794759 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature