Zhou Ji-Xiang, Yang Man-Yi, Zhai Deng-Gao, Jiang Qin, Zhang Qi
Department of Hepatobiliary and Pancreatic Surgery, Xiangya Hospital Central South University, Changsha, 410008, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, 410008, China.
Heliyon. 2024 Jul 30;10(15):e35467. doi: 10.1016/j.heliyon.2024.e35467. eCollection 2024 Aug 15.
Lipid accumulation and redox imbalance, resulting from dysregulation of hepatic fatty acids oxidation, contribute to the development of steatohepatitis and insulin resistance. Recently, dysregulated RNA N-methyladenosine (mA) methylation modification has been found involving fatty liver. However, the role of methyltransferase-like 14 (METTL14), the core component of mA methylation, in the development of steatohepatitis is unknown. Herein, we aimed to explore the role of METTL14 on steatohepatitis and insulin resistance in mice with metabolic dysfunction-associated steatotic liver disease (MASLD).
The liver tissues of mice and patients with MASLD were collected to detect the expression of METTL14. METTL14 overexpression and METTL14 silence were used to investigate the effect of METTL14 on lipid metabolism disorder and . Knockout of METTL14 in primary hepatocytes was used to investigate the role of Sirtuin 1 (SIRT1) on lipid accumulation induced by METTL14.
METTL14 was dramatically up-regulated in the livers of db/db mice, high-fat diet (HFD)-fed mice, and patients with MASLD. METTL14 overexpression exacerbated MASLD and promoted lipid metabolism disorder and insulin resistance in mice. Conversely, METTL14 knockout ameliorated lipid deposition and insulin resistance in HFD-fed mice. Furthermore, METTL14 overexpression facilitated lipid accumulation, while METTL14 knockout reduced lipid accumulation in HepG2 cells and primary hepatocytes. In addition, METTL14 lost up-regulated SIRT1 expression in hepatocytes. SIRT1 deficiency abrogated the ameliorating effects of METTL14 downregulation in MASLD mice.
These findings suggest that dysfunction of the METTL14-SIRT1 pathway might promote hepatic steatosis and insulin resistance.
肝脏脂肪酸氧化失调导致的脂质蓄积和氧化还原失衡，促进了脂肪性肝炎和胰岛素抵抗的发展。最近，已发现失调的RNA N-甲基腺苷（m⁶A）甲基化修饰与脂肪肝有关。然而，m⁶A甲基化的核心成分甲基转移酶样14（METTL14）在脂肪性肝炎发展中的作用尚不清楚。在此，我们旨在探讨METTL14在代谢功能障碍相关脂肪性肝病（MASLD）小鼠的脂肪性肝炎和胰岛素抵抗中的作用。
收集MASLD小鼠和患者的肝脏组织以检测METTL14的表达。采用METTL14过表达和METTL14沉默来研究METTL14对脂质代谢紊乱的影响。在原代肝细胞中敲除METTL14以研究沉默调节蛋白1（SIRT1）在METTL14诱导的脂质蓄积中的作用。
在db/db小鼠、高脂饮食（HFD）喂养的小鼠和MASLD患者的肝脏中，METTL14显著上调。METTL14过表达加剧了MASLD，并促进了小鼠的脂质代谢紊乱和胰岛素抵抗。相反，敲除METTL14可改善HFD喂养小鼠的脂质沉积和胰岛素抵抗。此外，METTL14过表达促进了脂质蓄积，而敲除METTL14则减少了HepG2细胞和原代肝细胞中的脂质蓄积。此外，METTL14缺失上调了肝细胞中SIRT1的表达。SIRT1缺乏消除了METTL14下调对MASLD小鼠的改善作用。
这些发现表明，METTL14-SIRT1通路功能障碍可能促进肝脏脂肪变性和胰岛素抵抗。
