Sterol Regulatory Element-Binding Protein 1 Is Negatively Modulated by Protein Kinase A Phosphorylation

Sterol regulatory element binding protein (SREBP) 1a and 1c are key transcription factors that regulate lipid biosynthesis in cells. We identified that Ser-338 located at the N-terminus of SREBP1a is a protein kinase A (PKA) phosphorylation site in vitro and in HepG2 cells. PKA phosphorylation of this site attenuated DNA occupancy, as revealed by ChIP assay, and the ensuing transactivation. In contrast, replacing Ser with Ala [SREBP1a(N)-S338A], increased the transactivation. Although forming heterodimers with the wild-type SREBP1a(N) or S338A but not a homodimer with itself, SREBP1a(N)-S338D (replacing Ser with Asp) decreased DNA binding. Ser-314 of SREBP1c, the counterpart of SREBP1a Ser-338, was also phosphorylated by PKA. Accordingly, the adenovirus-mediated expression of SREBP1c(N)-S314D in HepG2 cells retarded lipogenesis. Our results indicate that cAMP/PKA pathway, by phosphorylating SREBP1, may modulate lipid metabolism in liver cell lines.