Liver-specific microRNA-185 knockout promotes cholesterol dysregulation in mice.
Liver-specific microRNA-185 knockout promotes cholesterol dysregulation in mice.
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肝特异性microRNA-185敲除促进小鼠的胆固醇失调。
DOI：
10.1016/j.livres.2020.09.001
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Li T
中科院分区：
文献类型：
--
作者：
Chen C;Matye D;Wang Y;Li T
肝脏在调节全身胆固醇稳态中起着关键作用。肝脏胆固醇积累会导致脂肪肝疾病的肝损伤，而高胆固醇血症会增加心血管疾病的风险。 MicroRNA（miRNA、miR）已被证明可以调节胆固醇代谢的多种途径。最近，miR-185已被证明可以调节甾醇调节元件结合蛋白2（SREBP2）和低密度脂蛋白受体（LDLR）来调节胆固醇的合成和摄取。在肝脏特异性 miRNA-185 敲除 (L-miR-185 KO) 小鼠中研究了 miR-185 在调节饮食诱导的代谢紊乱中的作用。 L-miR-185 KO小鼠在高脂肪高胆固醇西方饮食喂养后出现更严重的肝脏脂肪变性，肝脏中甘油三酯和胆固醇积累。此外，L-miR-185 KO 小鼠在西方饮食喂养后出现高胆固醇血症。基因表达分析显示，L-miR-185 KO 小鼠并未表现出 SREBP2 或其靶标 LDLR 和 HMG-CoA 还原酶 (HMGCR) 肝脏 mRNA 表达增加。尽管miR-185模拟物的表达抑制HepG2细胞中SREBP2、HMGCR和LDLR的mRNA，但miR-185抑制剂并没有增加HepG2细胞中SREBP2、HMGCR或LDLR的mRNA。总之，我们报道L-miR-185 KO小鼠对西方饮食诱导的肝脂肪变性和高胆固醇血症更敏感。这些代谢变化背后的分子机制仍有待在未来的研究中进行研究。
The liver plays a key role in regulating whole body cholesterol homeostasis. Hepatic cholesterol accumulation causes liver injury in fatty liver disease and hypercholesterolemia increases the risk of cardiovascular disease. MicroRNAs (miRNAs, miRs) have been shown to regulate various pathways in cholesterol metabolism. Recently, miR-185 has been shown to regulate sterol regulatory element-binding protein 2 (SREBP2) and low-density lipoprotein receptor (LDLR) to modulate cholesterol synthesis and uptake. The role of miR-185 in regulating diet-induced metabolic disorders were studied in liver-specific miRNA-185 knockout (L-miR-185 KO) mice. L-miR-185 KO mice developed worsened hepatic steatosis upon high fat high cholesterol Western diet feeding with accumulation of triglyceride and cholesterol in the liver. In addition, L-miR-185 KO mice developed hypercholesterolemia upon Western diet feeding. Gene expression analysis showed that L-miR-185 KO mice did not show increased hepatic mRNA expression of SREBP2 or its targets LDLR and HMG-CoA reductase (HMGCR). Although expression of miR-185 mimic inhibited the mRNA of SREBP2, HMGCR and LDLR in HepG2 cells, miR-185 inhibitor did not increase the mRNA of SREBP2, HMGCR or LDLR in HepG2 cells. In conclusion, we reported that L-miR-185 KO mice were more sensitive to Western diet induced hepatic steatosis and hypercholesterolemia. The molecular mechanisms underlying these metabolic changes remain to be investigated in future studies.