TY - JOUR
T1 - MicroRNA-206-3p suppresses hepatic lipogenesis and cholesterol synthesis while driving cholesterol efflux
AU - Liu, Ningning
AU - Tian, Jing
AU - Steer, Clifford J.
AU - Han, Qinghua
AU - Song, Guisheng
N1 - Publisher Copyright:
Copyright © 2023 American Association for the Study of Liver Diseases.
PY - 2025/1/1
Y1 - 2025/1/1
N2 - 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.
AB - 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.
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U2 - 10.1097/hep.0000000000000672
DO - 10.1097/hep.0000000000000672
M3 - Article
C2 - 37943861
AN - SCOPUS:85199914435
SN - 0270-9139
VL - 81
SP - 111
EP - 125
JO - Hepatology (Baltimore, Md.)
JF - Hepatology (Baltimore, Md.)
IS - 1
ER -