Inhibition of miR-486 and miR-92a decreases liver and plasma cholesterol levels by modulating lipid-related genes in hyperlipidemic hamsters

Abstract

In the present study we aimed to evaluate the potential of in vivo inhibition of miR-486 and miR-92a to reverse hyperlipidemia, then to identify and validate their lipid metabolism-related target genes. Male Golden-Syrian hamsters fed a hyperlipidemic (HL) diet (standard chow plus 3% cholesterol and 15% butter, 10 weeks) were injected subcutaneously with lock-nucleic acid inhibitors for either miR-486 or miR-92a. Lipids and miRNAs levels in liver and plasma, and hepatic expression of miRNAs target genes were assessed in all HL hamsters. MiR-486 and miR-92a target genes were identified by miRWalk analysis and validated by 3'UTR cloning in pmirGLO vectors. HL hamsters had increased liver (2.8-fold) and plasma (twofold) miR-486 levels, and increased miR-92a (2.8-fold and 1.8-fold, respectively) compared to normolipidemic hamsters. After 2 weeks treatment, liver and plasma cholesterol levels decreased (23 and 17.5% for anti-miR-486, 16 and 22% for miR-92a inhibition). Hepatic triglycerides and non-esterified fatty acids content decreased also significantly. Bioinformatics analysis and 3'UTR cloning in pmirGLO vector showed that sterol O-acyltransferase-2 (SOAT2) and sterol-regulatory element binding transcription factor-1 (SREBF1) are targeted by miR-486, while ATP-binding cassette G4 (ABCG4) and Niemann-Pick C1 (NPC1) by miR-92a. In HL livers and in cultured HepG2 cells, miR-486 inhibition restored the levels of SOAT2 and SREBF1 expression, while anti-miR-92a restored ABCG4, NPC1 and SOAT2 expression compared to scrambled-treated HL hamsters or cultured cells. In vivo inhibition of miR-486 and miR-92a could be a useful and valuable new approach to correct lipid metabolism dysregulation.

Simultaneous miRNA and mRNA Transcriptome Profiling of Differentiating Equine Satellite Cells Treated with Gamma-Oryzanol and Exposed to Hydrogen Peroxide

“…Jentzsch et al [80] showed that this miRNA regulates cell size (hypertrophy) and increases protein synthesis in primary cardiomyocytes. Other interesting miRNA include miR-92a, which was shown to affect cholesterol metabolism and decrease liver and plasma cholesterol levels by modulating lipid-related genes in hamsters [81]. This miRNA is also related to the biosynthesis of insulin in rats [82].…”

Circulating microRNA Associated to Different Stages of Liver Steatosis in Prader–Willi Syndrome and Non-Syndromic Obesity

“…In particular, ABCG4 is responsible for the cholesterol loading into HDL particles [25] and its inhibition causes a defective cholesterol efflux to HDL [26]. The inhibition of miR-92-3p and the concomitant increased expression of the two targets reduced cholesterol levels in liver and plasma [24]. Interestingly, PWS subjects with lower mir-92a-3p expression show significantly higher HDL cholesterol levels (p = 0.01), although no significant correlation was found.…”

“…As previously discussed [17], miR-122-5p is one of the hepatic hallmarks with key roles in lipid metabolism and trafficking. The molecular function of miR-92a-3p, previously known as mir-92a, was recently elucidated in a work by Niculescu LS et al [24] in which, by targeting ABCG4 and NPC1, miR-92-3p was shown to impair cholesterol efflux from cells. In particular, ABCG4 is responsible for the cholesterol loading into HDL particles [25] and its inhibition causes a defective cholesterol efflux to HDL [26].…”

Advancements in microRNA research in dyslipidemia

“…HepG2细胞 调节LDLR及PCSK9 LDLR mRNA, PCSK9 mRNA Alvarez等人 [49] miR-27b Huh7细胞 -ANGPTL3 Vickers等人 [50] miR-98 肝脏 -SREBP2 Geng等人 [51] miR-486 肝脏 -SREBP1 Niculescu等人 [30] miR-142a-5p 肝脏 -SREBP1c Zhong等人 [52] miR-30c 肝脏 抑制MTP MTP, 脂质合成基因 Irani等人 [53] miR-548p 人肝细胞 抑制ApoB ApoB mRNA Zhou和Hussain [54] miR-98-5-p 肝脏 -PGC-1β Chen等人 . miR-142a-5p则作用于肝脏SREBP1c, 抑制肝脏 脂质沉积 [52] .…”