Rong S, Cortés VA, Rashid S et al.
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.
eLife. Feb 2017.
The synthesis of cholesterol and fatty acids (FA) in liver is independently regulated by SREBP-2 and SREBP-1c, respectively. Here we genetically deleted Srebf-2 from hepatocytes and confirmed that SREBP-2 regulates all genes involved in cholesterol biosynthesis, the LDL receptor, and PCSK9; a secreted protein that degrades LDL receptors in liver. Surprisingly, we found that elimination of Srebf-2 in hepatocytes of mice also markedly reduced SREBP-1c and the expression of all genes involved in FA and triglyceride synthesis that are normally regulated by SREBP-1c. The nuclear receptor LXR is necessary for Srebf-1c transcription. The deletion of Srebf-2 and subsequent lower sterol synthesis in hepatocytes eliminated the production of an endogenous sterol ligand required for LXR activity and SREBP-1c expression. These studies demonstrate that cholesterol and FA synthesis in hepatocytes are coupled and that flux through the cholesterol biosynthetic pathway is required for maximal SREBP-1c expression and high rates of FA synthesis.