Control of Cholesterol Metabolism and Plasma High-Density Lipoprotein Levels by microRNA-144

Abstract

Rationale Foam cell formation due to excessive accumulation of cholesterol by macrophages is a pathological hallmark of atherosclerosis, the major cause of morbidity and mortality in Western societies. Liver X nuclear receptors (LXRs) regulate the expression of the adenosine triphosphate-binding cassette (ABC) transporters, including ABCA1 and ABCG1. ABCA1 and ABCG1 facilitate the efflux of cholesterol from macrophages and regulate high-density lipoprotein (HDL) biogenesis. Increasing evidence supports the role of microRNA (miRNAs) in regulating cholesterol metabolism through ABC transporters. Objective We aimed to identify novel miRNAs that regulate cholesterol metabolism in macrophages stimulated with LXR agonists. Methods and Results To map the miRNA expression signature of macrophages stimulated with LXR agonists, we performed a miRNA profiling microarray analysis in primary mouse peritoneal macrophages stimulated with LXR ligands. We report that LXR ligands increase miR-144 expression in macrophages and mouse livers. Overexpression of miR-144 reduces ABCA1 expression and attenuates cholesterol efflux to ApoA1 in macrophages. Delivery of miR-144 oligonucleotides to mice attenuates ABCA1 expression in the liver, reducing HDL levels. Conversely, silencing of miR-144 in mice increases the expression of ABCA1 and plasma HDL levels. Thus, miR-144 appears to regulate both macrophage cholesterol efflux and HDL biogenesis in the liver. Conclusions 1) miR-144 regulates cholesterol metabolism via suppressing ABCA1 expression; and 2) modulation of miRNAs may represent a potential therapeutical intervention for treating dyslipidemia and atherosclerotic vascular disease.

WITHDRAWN: An integrated analysis of microRNAs involved in fat deposition in different pig breeds

“…The depressed expression of miR-122 effectively reduces the cholesterol content in the serum [44]. Furthermore, the targeted control of ssc-miR-144 and ssc-miR-758 to the ATP-binding cassette sub-family A member 1 (ABCA1) gene results in an indirect regulation of the metabolism of cholesterol [45,46]. ssc-miR-204 inhibits the Runx2 gene, thus, accelerating the adipogenic differentiation of MPCs and BMSCs [47], and the upregulation of ssc-miR-204, in this study, indicates that it may activate adipocyte differentiation in pigs.…”

Characterization of microRNAs differentially expressed during bovine follicle development

“…The present result of a greater than fourfold increase in bta-miR-202 levels between 9-11 and 15-17 mm healthy follicles builds on those earlier findings by indicating a role for this miRNA during folliculogenesis in the adult bovine ovary. In addition to mir-202, biological roles for the clustered mir-144 and mir-451 have also been proposed, but only in relation to non-ovarian cells; those include regulatory roles in erythropoiesis (Pase et al 2009), differentiation of vascular smooth muscle cells (Turczyń ska et al 2013) and, potentially relevant during follicular differentiation, cholesterol trafficking in macrophages (Ramirez et al 2013). Interestingly, both miR-144 and miR-451, as well as miR-652, were upregulated in rat ovaries following an ovulatory hCG bolus, although no attempt was made to identify the specific cell type(s) involved (Kitahara et al 2013).…”

Liver X Receptors and their Agonists: Targeting for Cholesterol Homeostasis and Cardiovascular Diseases

“…Moreover, Ramírez and colleagues demonstrated that T0901317 increases miR-144 expression in macrophages and mouse livers. The overexpression of miR-144 reduces ABCA1 expression, while the silencing of miR-144 in mice increases the expression of ABCA1 and plasma HDL levels (Ramirez et al, 2013). Thus,…”