Hepatic miR-378 modulates serum cholesterol levels by regulating hepatic bile acid synthesis

Abstract

Rationale: An improved understanding of thyroid hormone (TH) action on cholesterol metabolism will facilitate the identification of novel therapeutic targets for hypercholesterolemia. TH-regulated microRNAs (miRNAs) have been implicated in TH-controlled biological processes; however, whether and how TH-regulated miRNAs mediate the cholesterol-lowering effect of TH remains unclear. Our aim was to identify TH-regulated microRNAs that have cholesterol-lowering effects and explore the underlying mechanism. Method: Microarray and RNA-seq were performed to identify TH-regulated microRNAs and the genes regulated by mmu-miR-378-3p (miR-378) in the liver of mice, respectively. Recombinant adenoviruses encoding miR-378, Mafg , and shRNA for Mafg , antagomiR-378, liver-specific miR-378 transgenic mice, and miR-378 knockout mice were employed to investigate the roles of hepatic miR-378 and MAFG in cholesterol and bile acid homeostasis. The levels of bile salt species were determined by using UFLC-Triple-time of flight/MS. Results: Here, we show that hepatic miR-378 is positively regulated by TH. Transient overexpression of miR-378 in the liver of mice reduces serum cholesterol levels, accompanied with an increase in the expression of key enzymes in primary bile acid synthetic pathways and corresponding increases in biliary and fecal bile acid levels. Consistently, liver-specific miR-378 transgenic mice with moderate overexpression of hepatic miR-378 display decreased serum cholesterol levels and resistance to diet-induced hypercholesterolemia, while mice lacking miR-378 exhibit defects in bile acid and cholesterol homeostasis. Mechanistically, hepatic miR-378 regulates the expression of key enzymes in both classic and alternative bile acid synthetic pathways through MAFG, a transcriptional repressor, thereby modulating bile acid and cholesterol metabolism. Conclusions: TH-responsive hepatic miR-378 is capable of modulating serum cholesterol levels by regulating both the classic and alternative BA synthetic pathways. Our study not only identifies a previously undescribed role of hepatic miR-378 but also provides new cholesterol-lowering approaches.

Update on dyslipidemia in hypothyroidism: the mechanism of dyslipidemia in hypothyroidism

“…SOAT2 is essential for converting cholesterol into cholesterol ester (CE), and the latter is the preferred form of LDL ( 85 ); and TH mediated the reduction of miR-206, so TG and TC in HepG2 cells declined ( 86 ). Also, TH could positively regulate hepatic miR-378, leading to the reduction of serum cholesterol levels through promoting bile acid synthetic pathways ( 87 ). Recently, a regulatory module containing three miRNAs (miR-34a-5p, miR-24-3p and miR-130a-3p) and four proteins (thioredoxin, selenium-binding protein 2, elongation factor 1β and prosaposin) about hepatic lipid metabolism was identified in subclinical mice ( 88 ).…”

Multiple transcriptome analyses reveal mouse testis developmental dynamics

“…Nine miRNAs were involved in the ceRNA interactions, but none of them showed associations with testicular development. Sun et al [ 60 ] report that the mice lacking miR-378 have defects in cholesterol homeostasis. In this study, the expression level of cholesterol side-chain cleavage enzyme (CYP11A1) increased from 8.62 FPKM to 52.33 FPKM, so we assumed that differentially expressed miR-378 might provide conditions for the following spermatogenesis by maintaining cholesterol homeostasis.…”

MicroRNA Expression in Patients with Coronary Artery Disease and Hypertension—A Systematic Review

“…Furthermore, miR-378 has been implicated in regulating osteogenic differentiation and follicle development [ 41 ]. Studies have also shown that miR-378 can modulate cholesterol levels, suppress hepatoma cell growth, and induce apoptosis in cancer cells [ 40 , 42 ].…”