MicroRNA-200c coordinates HNF1 homeobox B and apolipoprotein O functions to modulate lipid homeostasis in alcoholic fatty liver disease.
MicroRNA-200c coordinates HNF1 homeobox B and apolipoprotein O functions to modulate lipid homeostasis in alcoholic fatty liver disease.
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DOI：
10.1016/j.jbc.2022.101966
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发表时间：
2022-06
影响因子：
4.8
通讯作者：
Shin, Dong-Ju
中科院分区：
文献类型：
--
作者：
Mostofa, Golam;Tran, Melanie;Gilling, Shaynian;Lee, Grace;Fraher, Ondine;Jin, Lei;Kang, Hyunju;Park, Young-Ki;Lee, Ji-Young;Wang, Li;Shin, Dong-Ju
肝脏脂肪变性是酒精性肝病的最初表现。肝脏脂质过程的不平衡，包括脂肪酸摄取、酯化、氧化和甘油三酯分泌，会导致酒精性脂肪肝 (AFL)。然而，AFL 发病机制的精确分子机制仍然难以捉摸。在这里，我们发现缺乏 microRNA (miR)-141 和 -200c 的小鼠表现出对 AFL 发展的抵抗力。我们发现 miR-200c 直接靶向 HNF1 同源盒 B (Hnf1b)，微粒体甘油三酯转移蛋白 (Mttp) 的转录激活剂，以及载脂蛋白 O (ApoO)，线粒体接触位点和嵴组织系统复合体的组成部分。我们发现，慢性乙醇暴露显着诱导这些 miR 的表达，同时伴随着 HNF1B 和 APOO 水平的降低。此外，miR-141/200c 缺陷使乙醇介导的甘油三酯分泌损伤正常化，这可归因于 HNF1B 和 MTTP 水平以及磷脂酰胆碱丰度的恢复。此外，我们证明 miR-141/200c 缺陷可以恢复乙醇介导的 APOO 表达和线粒体功能障碍的抑制，从而改善线粒体抗氧化防御能力和脂肪酸氧化。综上所述，这些结果表明 miR-200c 通过协同调节 Hnf1b 和 ApoO 功能，有助于调节 AFL 疾病中的脂质稳态。
Hepatic steatosis is an initial manifestation of alcoholic liver disease. An imbalance of hepatic lipid processes including fatty acid uptake, esterification, oxidation, and triglyceride secretion leads to alcoholic fatty liver (AFL). However, the precise molecular mechanisms underlying the pathogenesis of AFL remain elusive. Here, we show that mice deficient in microRNAs (miRs)-141 and -200c display resistance to the development of AFL. We found that miR-200c directly targets HNF1 homeobox B (Hnf1b), a transcriptional activator for microsomal triglyceride transfer protein (Mttp), as well as apolipoprotein O (ApoO), an integral component of the mitochondrial contact site and cristae organizing system complex. We show that expression of these miRs is significantly induced by chronic ethanol exposure, which is accompanied by reduced HNF1B and APOO levels. Furthermore, miR-141/200c deficiency normalizes ethanol-mediated impairment of triglyceride secretion, which can be attributed to the restored levels of HNF1B and MTTP, as well as phosphatidylcholine abundance. Moreover, we demonstrate that miR-141/200c deficiency restores ethanol-mediated inhibition of APOO expression and mitochondrial dysfunction, improving mitochondrial antioxidant defense capacity and fatty acid oxidation. Taken together, these results suggest that miR-200c contributes to the modulation of lipid homeostasis in AFL disease by cooperatively regulating Hnf1b and ApoO functions.
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影响因子：
1.4
作者：
Chen, L.;Ilham, S. J.;Feng, B.
通讯作者：
Feng, B.
影响因子：
5
作者：
Attal N;Sullivan MT;Girardi CA;Thompson KJ;McKillop IH
通讯作者：
McKillop IH
影响因子：
5.4
作者：
Grygiel-Górniak B
通讯作者：
Grygiel-Górniak B
影响因子：
5.3
作者：
Hayhurst, GP;Lee, YH;Gonzalez, FJ
通讯作者：
Gonzalez, FJ
影响因子：
4.8
作者：
Jacobs, RL;Devlin, C;Vance, DE
通讯作者：
Vance, DE