The nuclear receptor FXR uncouples the actions of miR-33 from SREBP-2

Abstract

Objective - To determine whether activation of farnesoid X receptor (FXR) alters cellular and plasma cholesterol homeostasis as a result of regulation of Srebp-2 and miR-33. Approach and Results - Chromatin immunoprecipitation sequencing data identified an FXR response element within intron 10 of the Srebp-2 gene. Consistent with this observation, treatment of mice with FXR-specific agonists (GSK2324 or GW4064) rapidly increased hepatic levels of Srebp-2 mRNA, precursor sterol response element binding protein 2 (pSREBP-2) protein, and miR-33. Furthermore, miR-33 targets, that include ABCA1 (ATP binding cassette transporter A1), NSF (N-ethylmaleimide-sensitive factor), and CPT1 (carnitine palmitoyltransferase 1), were all reduced in GSK2324-treated mice. In contrast, neither nuclear SREBP-2 protein (nSREBP-2) nor SREBP-2 target genes were induced after FXR activation. The inability to process pSREBP-2 to nSREBP-2 is likely a consequence of the induction of insulin INSIG-2A (induced gene 2A) by FXR agonists. Finally, we show that FXR-dependent induction of both Srebp-2 and miR-33 is ablated in Scap-/- mice that lack nuclear SREBP-2. Conclusions - We demonstrate that the activation of FXR uncouples the expression of nuclear SREBP-2 and miR-33, and the regulation of their respective target genes. Further, we conclude that the FXR agonist-dependent increase in miR-33 requires transcription of the Srebp-2 gene.