Salt-inducible Kinase Regulates Hepatic Lipogenesis by Controlling SREBP-1c Phosphorylation

Liver plays a major role in regulating energy homeostasis in mammals. During feeding conditions, excessive glucose is converted into a preferred storage form of energy sources as triacylglycerol in liver via a collective metabolic pathway termed lipogenesis. Sterol regulatory element-binding protein 1c is a master regulator for this process by activating number of enzyme genes, such as Fasn or Acaca, that are involved in this pathway at the transcriptional level. Here we show that the salt-inducible kinase (SIK) family of proteins regulates the hepatic lipogenesis by modulating SREBP-1c activity. Overexpression of SIK1 inhibits hepatic expression of lipogenic genes, such as Fasn, whereas knockdown of SIK1 in liver greatly enhances their expression. Regulation of the Fasn gene by SIK kinases is mediated at the level of transcription via phosphorylation and inactivation of nuclear SREBP-1c. Among candidate sites for SIK-dependent regulation of SREBP-1c, the serine 329 residue is shown to be a critical regulatory site for SIK-mediated repression of SREBP-1c activity by in vitro kinase assay and reverse transcription-PCR analysis in primary hepatocytes. Finally, reduced hepatic triacylglycerol levels and lipogenic gene expression by adenoviral SIK1 transgenic expression are restored to normal levels by co-infection of mutant SREBP-1c, suggesting that SIK-dependent regulation of hepatic lipogenesis is indeed mediated through the phosphorylation of SREBP-1c in vivo. The process for the development of nonalcoholic fatty liver involves de novo lipogenesis via the activation of SREBP-1c. Modulation of SREBP-1c activity by SIK proteins would provide an attractive means for the regulation of such diseases.