MicroRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1) exhibit reduced HDL-C in vivo

Abstract

MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote mRNA degradation. Recent reports, including ours, indicated that miR-33a located within the intron of sterol regulatory element-binding protein (SREBP) 2 controls cholesterol homeostasis and can be a possible therapeutic target for treating atherosclerosis. Primates, but not rodents, express miR-33b from an intron of SREBF1. Therefore, humanized mice, in which a miR-33b transgene is inserted within a Srebf1 intron, are required to address its function in vivo. We successfully established miR-33b knock-in (KI) mice and found that protein levels of known miR-33a target genes, such as ABCA1, ABCG1, and SREBP-1, were reduced compared with those in wild-type mice. As a consequence, macrophages from the miR-33b KI mice had a reduced cholesterol efflux capacity via apoA-I and HDL-C. Moreover, HDL-C levels were reduced by almost 35% even in miR-33b KI hetero mice compared with the control mice. These results indicate that miR-33b may account for lower HDL-C levels in humans than those in mice and that miR-33b is possibly utilized for a feedback mechanism to regulate its host gene SREBF1. Our mice will also aid in elucidating the roles of miR-33a/b in different genetic disease models.

MicroRNA-33a/b in Lipid Metabolism

“…Moreover, we analyzed the liver and measured the serum lipid profile of miR-33b knock-in (KI) mice, which have miR-33b in the same intron as humans. 30 In contrast to the results with miR-33a-deficient mice, HDL-C levels in these mice were reduced by almost 35%, even in miR-33b KI hetero mice compared with the control mice ( Figures 3C,D).…”

“…[27][28][29][30] In this review, we summarize the functions of miR-33a/b and therapeutic strategies to suppress these functions.…”

MicroRNA-26a/b and their host genes synergistically regulate triacylglycerol synthesis by targeting theINSIG1gene

“…53 MiR-33a/b act in concert with SREBF2 to control cholesterol homeostasis. 14,17 Unlike other cells or tissues, there is limited information on the relationship between the miR-26 family and their host genes in lactating ruminant mammary gland. The current study revealed a strong positive relationship between the miR-26a/b and their host genes in goat mammary gland tissue, which is consistent with a previous study reporting that the miR-26a/b are expressed concomitantly with their host genes.…”

Dietary Regulation of miR-33b and miR-29a in Relationship to Metabolic Biomarkers of Glucose and Lipids in Obese Diabetic Women: A Randomized Clinical Controlled Study

“…While the same target activities have already been suggested for miR-33a and miR-33b, they have different patterns of evolutionary conservation (13,20). Studies exploring the effects of human miR-33b on glucose and lipid metabolism pathways are scarce.…”

“…MiR-33b is encoded in humans and other large mammals (13,20), but only limited studies have assessed it in human glucose homeostasis. Moreover, there are scarce studies exploring the impact of diet therapy on circulating miR-33b and miR-29a in obesity and T2DM.…”