MicroRNA-206-3p suppresses hepatic lipogenesis and cholesterol synthesis while driving cholesterol efflux

Ningning Liu; Jing Tian; Clifford J Steer; Qinghua Han; Guisheng Song

doi:10.1097/HEP.0000000000000672

MicroRNA-206-3p suppresses hepatic lipogenesis and cholesterol synthesis while driving cholesterol efflux

Hepatology. 2023 Nov 9. doi: 10.1097/HEP.0000000000000672. Online ahead of print.

Authors

Ningning Liu^{1

2}, Jing Tian³, Clifford J Steer^{2

4}, Qinghua Han³, Guisheng Song^{2

4}

Affiliations

¹ Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
² Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
³ Department of Cardiology, the First Hospital of Shanxi Medical University, Taiyuan City, China.
⁴ Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, USA.

PMID: 37943861
DOI: 10.1097/HEP.0000000000000672

Abstract

Background and aims: Hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia are interconnected metabolic disorders. This study is designed to characterize how microRNA-206-3p (miR-206) simultaneously prevents de novo lipogenesis (DNL), cholesterol synthesis, and VLDL production in hepatocytes while promoting cholesterol efflux in macrophages.

Approach and results: MiR-206 levels were reduced in hepatocytes and macrophages of mice subjected to a high-fat, high-cholesterol diet. A negative feedback between LXRα (liver X receptor alpha) and miR-206 is formed to maintain high LXRα and low miR-206 in hepatocytes. Systemic administration of miR-206 alleviated hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia in mice. A significant reduction in LDL cholesterol and VLDL cholesterol but unaltered HDL cholesterol was observed in miR-206-treated mice. Mirroring these findings, miR-206 reprogrammed the transcriptome of hepatocytes towards the inhibition of DNL, cholesterol synthesis, and assembly and secretion of VLDL. In macrophages, miR-206 activated the expression of genes regulating cholesterol efflux. Hepatocyte-specific expression of miR-206 reduced hepatic and circulating triglycerides and cholesterol, as well as VLDL production, while transplantation of macrophages bearing miR-206 facilitated cholesterol efflux. Mechanistically, miR-206 directly targeted Lxrα and Hmgcr in hepatocytes but facilitated expression of Lxrα in macrophages by targeting macrophage-specific tricho-rhino-phalangeal syndrome 1 (TRPS1), a transcription repressor of Lxrα . By targeting Hmgc r and Lxrα , miR-206 inhibited DNL, VLDL production, and cholesterol synthesis in hepatocytes, whereas it drove cholesterol efflux by activating the TRPS1-LXRα axis.

Conclusions: MiR-206, through differentially modulating LXRα signaling in hepatocytes and macrophages, inhibits DNL, promotes cholesterol efflux, and concurrently hinders cholesterol synthesis and VLDL production. MiR-206 simulates the functions of lipid-lowering medications, statins, and LXRα agonists.