SREBF2-embedded mir33 links the nuclear bile acid receptor FXR to cholesterol and lipoprotein metabolism.

1 identify a novel regulatory loop of hepatic cholesterol bio-synthesis 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 lipopro-tein (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. Cholesterol is an essential component of cell membranes and a precursor of numerous signaling molecules, from ste-roid 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 mechanism involving a sequential docking/release from the Golgi to the endoplasmic reticulum, they undergo proteolytic cleavage and subsequent nuclear translocation. Whereas the nuclear SREBP1 (nSREBP1) isoforms mainly regulate genes of the lipogenic pathway, nSREBP2 primarily regulates genes controlling cholesterol synthesis, such as HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase, and uptake, such as the LDL receptor. 3 Interestingly, the human SREBP–encoding loci SREBF1 and SREBF2 also contain cotranscriptionally regulated miR-NAs, respectively, miR-33b and miR33a, the latter being evolutionary conserved. 4 MiR33a plays a modulatory role in cholesterol homeostasis in rodents and primates, as its target transcripts include notably Abca1 and Abcg1 (Figure). The authors identified, by analyzing previously published mouse liver FXR ChIP-Seq (chromatin immunoprecipitation followed by sequencing) data, 5,6 an intronic FXR binding site within the Srebf2 locus, which confers FXR responsiveness to Srebf2 and mmu-mir33a. However, the FXR-mediated accumulation of the Srebf2 transcript was accompanied by neither increased nSREBP2 protein nor cholesterol biosynthesis target genes. This uncoupling between induction of Srebf2 transcription and nSREBP2 production is likely the result of FXR-induced transcription of Insig2a, a known FXR target gene whose product traps SREBPs into the endoplasmic reticulum 7. Whether mmu-mir33a transcription stems from a transcription unit independent of Srebf2 was investigated indirectly using liver-deficient Scap mice. SREBP cleavage activating protein (SCAP) deficiency phenotypically translates into impaired SREBP …