Abstract
The synthesis of cholesterol and fatty acids (FA) in the 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 the 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 the maximal SREBP-1c expression and high rates of FA synthesis.
Highlights
Cholesterol and fatty acid (FA) biosynthetic gene expression is regulated by the sterol regulatory element-binding protein (SREBP) family of transcription factors (Horton et al, 2002)
The results confirm that SREBP2 is required for normal levels of cholesterol biosynthetic gene expression, but unexpectedly, we found the expression of Srebf-1c and its target genes for FA and TG synthesis was dependent on SREBP-2 expression
The current data confirm that SREBP-2 is the primary transcriptional regulator of cholesterol biosynthesis in vivo
Summary
Cholesterol and fatty acid (FA) biosynthetic gene expression is regulated by the sterol regulatory element-binding protein (SREBP) family of transcription factors (Horton et al, 2002). The membrane-bound, inactive forms of SREBPs are located in the endoplasmic reticulum bound to Scap, an escort protein that serves as a sensor of cellular sterol levels (Brown and Goldstein, 2009). When cellular sterol levels are high, Scap binds an ER retention protein, Insig, which retains the SREBP/Scap complex in the ER. To generate the active nuclear form of SREBPs, SREBP/Scap dissociates from Insig, and the complex moves from the ER to the Golgi where two proteases, designated S1P and S2P, sequentially cleave SREBPs releasing the amino-terminal fragment, which travels to the nucleus to activate regulated genes
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