miR-33 links SREBP-2 induction to repression of sterol transporters

Abstract

The sterol regulatory element binding protein 2 (SREBP-2) and the liver X receptor (LXR) control antagonistic transcriptional programs that stimulate cellular cholesterol uptake and synthesis, and cholesterol efflux, respectively. The clinical importance of SREBP-2 is revealed in patients with hypercholesterolemia treated with statins, which reduce low-density lipoprotein (LDL) cholesterol levels by increasing hepatic expression of SREBP-2 and its target, the LDL receptor. Here we show that miR-33 is encoded within SREBP-2 and that both mRNAs are coexpressed. We also identify sequences in the 3′ UTR of ABCA1 and ABCG1, sterol transporter genes both previously shown to be regulated by LXR, as targets for miR-33-mediated silencing. Our data show that LXR-dependent cholesterol efflux to both ApoAI and serum is ameliorated by miR-33 overexpression and, conversely, stimulated by miR-33 silencing. Finally, we show that ABCA1 mRNA and protein and plasma HDL levels decline after hepatic overexpression of miR-33, whereas they increase after hepatic miR-33 silencing. These results suggest novel ways to manage hypercholesterolemic patients.

Post-transcriptional regulation in metabolic diseases

“…SREBPs are helix-loophelix-leucine zipper transcription factors that play critical roles in cholesterol biosynthesis, while miR-33a and miR-33b, encoded within the introns of the srebp-2 and srebp-1 genes, respectively, are highly conserved and ubiquitously expressed miRNAs. 65 Recently, it was reported that miR-33a/b are co-regulated with their host genes under metabolic stimuli and they were identified as critical regulators of cholesterol homeostasis by three different groups. [65][66][67][68] In mouse and human, miR-33 inhibited the expression of the ABCA1, thereby inhibiting cholesterol trafficking.…”

“…65 Recently, it was reported that miR-33a/b are co-regulated with their host genes under metabolic stimuli and they were identified as critical regulators of cholesterol homeostasis by three different groups. [65][66][67][68] In mouse and human, miR-33 inhibited the expression of the ABCA1, thereby inhibiting cholesterol trafficking. Overexpression of miR-33 in macrophages and hepatocytes decreased cholesterol efflux to apoA1, while inhibition of miR-33 resulted in increased ABCA1 expression and cholesterol efflux.…”

“…In mouse macrophages, miR-33 also regulated ABCG1, which mobilized cellular free cholesterol to high density lipoprotein (HDL) particles. 65,66 In human macrophages and hepatocytes, miR-33 regulated the expression of the protein NPC1 (Neimann Pick C1), which acts in concert with ABCA1 to cause efflux of cholesterol to apoA1, suggesting that miR-33 suppresses another component of the cholesterol export pathway in humans. 66 It was further demonstrated that miR-33 also affects β-oxidation of fatty acids by targeting CPT1a, CROT and HADHB, which are critical enzymes in the β-oxidation pathway.…”

miR-148a and miR-17–5p synergistically regulate milk TAG synthesis via PPARGC1A and PPARA in goat mammary epithelial cells

“…2,46 The nutritional value of goat milk, especially fat composition and content ( 15,44 , can be further enhanced through dietary manipulation. 25,27,43 As a result, there have been several research studies on the molecular mechanisms regulating milk fat synthesis; however, they have been primarily focused on analyses of single gene function ( 20,54,61 .…”

MicroRNAs in Cardiometabolic Diseases

“…Specifically, miR-33a has been shown to target genes involved in cholesterol export, such as the ABC transporters ABCA1 and ABCG1 (46)(47)(48) and the endolysosomal transport protein Niemann-Pick C1 (Npc1). (48) In agreement with the regulation of ABCA1 by miR-33, modulation of miR-33a levels results in encompassing effects in cholesterol efflux in macrophages, thus suggesting that miR-33 may participate in the regulation of HDL levels in vivo.…”