SREBF2 -Embedded mir33 Links the Nuclear Bile Acid Receptor FXR to Cholesterol and Lipoprotein Metabolism

In their article, published in the present issue, Tarling et al1 identify a novel regulatory loop of hepatic cholesterol biosynthesis and export in mice involving the nuclear bile acid receptor FXR/NR1H4. Through transcriptional regulation of the Srebf2 gene and its intronic microRNA mmu-miR33 , FXR is now shown to participate in cholesterol homeostasis by post-transcriptional silencing of mir33 targets, including Abca1 , a major determinant of hepatic high-density lipoprotein (HDL) production.2 This mechanism reveals another level of integration of lipid and cholesterol metabolism by FXR, as this bile acid–activated transcription factor is already known to control the expression of genes involved in triglyceride metabolism and the enterohepatic cycling of bile acids, which are cholesterol catabolites.See accompanying article on page 787 Cholesterol is an essential component of cell membranes and a precursor of numerous signaling molecules, from steroid hormones to bile acids. Its synthesis, dietary absorption, and distribution throughout the body are tightly regulated processes as elevated cholesterol concentrations, notably in the low-density lipoprotein (LDL) fraction, increases the risk for cardiovascular disease. The basic helix-loop-helix leucine zipper transcription factors, sterol-regulatory element binding proteins (SREBPs), are key regulators of fatty acid and cholesterol homeostasis. Activated at low cellular cholesterol concentrations through a …