BACKGROUND AND AIMS Hepatosteatosis, hypertriglyceridemia, and hypertriglyceridemia 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 (HFHC). A negative feedback between LXRα (liver X receptor) 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 inhibition of DNL, cholesterol synthesis, and assembly and secretion of VLDL. In macrophages, miR-206 activated 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 TRPS1 (tricho-rhino-phalangeal syndrome 1), a transcription repressor of Lxrα. By targeting Hmgcr 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.

中文翻译：

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MicroRNA-206-3p 抑制肝脏脂肪生成和胆固醇合成，同时驱动胆固醇流出。

背景和目的 肝脂肪变性、高甘油三酯血症和高甘油三酯血症是相互关联的代谢紊乱。本研究旨在表征 microRNA-206-3p (miR-206) 如何同时阻止肝细胞中的从头脂肪生成 (DNL)、胆固醇合成和 VLDL 产生，同时促进巨噬细胞中的胆固醇流出。方法和结果 接受高脂肪、高胆固醇饮食 (HFHC) 的小鼠肝细胞和巨噬细胞中的 MiR-206 水平降低。LXRα（肝脏X受体）和miR-206之间形成负反馈，以维持肝细胞中的高LXRα和低miR-206。全身给予 miR-206 可减轻小鼠的肝脂肪变性、高甘油三酯血症和高胆固醇血症。在 miR-206 治疗的小鼠中观察到 LDL 胆固醇和 VLDL 胆固醇显着降低，但 HDL 胆固醇未改变。与这些发现相呼应的是，miR-206 对肝细胞的转录组进行了重新编程，以抑制 DNL、胆固醇合成以及 VLDL 的组装和分泌。在巨噬细胞中，miR-206 激活调节胆固醇流出的基因表达。miR-206 的肝细胞特异性表达减少了肝脏和循环中的甘油三酯和胆固醇以及 VLDL 的产生，而携带 miR-206 的巨噬细胞的移植则促进了胆固醇的流出。从机制上讲，miR-206直接靶向肝细胞中的Lxrα和Hmgcr，但通过靶向巨噬细胞特异性TRPS1（毛犀指骨综合征1）（Lxrα的转录抑制因子）促进巨噬细胞中Lxrα的表达。通过靶向 Hmgcr 和 Lxrα，miR-206 抑制肝细胞中的 DNL、VLDL 产生和胆固醇合成，同时通过激活 TRPS1-LXRα 轴驱动胆固醇流出。结论 MiR-206 通过差异调节肝细胞和巨噬细胞中的 LXRα 信号传导，抑制 DNL，促进胆固醇外流，同时阻碍胆固醇合成和 VLDL 产生。MiR-206 模拟降脂药物、他汀类药物和 LXRα 激动剂的功能。