The Functional Interaction Between PRDM16 and the SREBP Pathway Controls Lipid Metabolism

Dysregulated lipid metabolism is associated with cardiovascular disease, obesity and type 2 diabetes. In the current report, we explore the functional interactions between two important regulators of lipid metabolism, sterol regulatory element-binding protein 1 and 2 (SREBP1/2), and PRDI-BF1 and RIZ homology domain containing 16 (PRDM16). The SREBP family of transcription factors regulate cholesterol and fatty acid synthesis and metabolism, primarily in liver but also in white adipose tissue. PRDM16 is a major regulator of brown adipose tissue (BAT) biogenesis and function as well as an inhibitor of white adipogenesis. We find that PRDM16 interacts with the nuclear forms of SREBP1/2 and inhibits their transcriptional activities. Consequently, inactivation of PRDM16 enhances the expression of well-established SREBP target genes involved in fatty acid and cholesterol synthesis/metabolism. Importantly, PRDM16 inactivation increases the expression of LDL receptor mRNA (1.6-fold) and protein (1.7-fold) and augments the cellular uptake of LDL particles (2.3-fold). Supporting these findings, PRDM16-deficient cells accumulate more neutral lipids in a SREBP1/2-dependent manner. Inactivation of PRDM16 in white and brown preadipocyte cell lines and human adipose-derived stem cells enhances the expression of SREBP target genes. In addition, the expression of adipogenic markers was increased in mature white adipocytes generated from PRDM16-knockdown preadipocytes (1.8- to 3.9-fold). Thus, our study identifies PRDM16 as a novel inhibitor of SREBP-dependent lipid metabolism with implications for adipose biology and metabolic disease.