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肝脏中生物钟基因的敲低通过抑制脂质自噬加重小鼠的代谢相关脂肪性肝病。

Knockdown of the Clock gene in the liver aggravates MASLD in mice via inhibiting lipophagy.

作者信息

Yang Shuhong, Ren Xinxin, Liu Jia, Lei Yan, Li Minqian, Wang Fang, Cheng Shuting, Ying Junjie, Ding Jie, Chen Xiaohui

机构信息

School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou, Gansu, 730050, People's Republic of China.

NHC Key Laboratory of Chronobiology, Sichuan University, Chengdu, 610041, Sichuan, China.

出版信息

Mol Cell Biochem. 2025 Apr;480(4):2455-2469. doi: 10.1007/s11010-024-05109-7. Epub 2024 Sep 14.

DOI:10.1007/s11010-024-05109-7
PMID:39276171
Abstract

The increased global prevalence of metabolic dysfunction-associated steatohepatitis (MASLD) has been closely associated with chronic disorders of the circadian clock. Herein, we investigate the role of Clock, a core circadian gene, in the pathogenesis of MASLD. Wild-type (WT) and liver-specific Clock knockdown (Clock-KD) mice were fed a Western diet for 20 weeks to induce MASLD. A cellular MASLD model was established by treating AML12 cells with free fatty acids and the effects of Clock knockdown were examined following transfection with Clock siRNA. Increased lipid deposition and more severe steatohepatitis and fibrosis were observed in the livers of Western diet-fed but not normal chow diet-fed Clock-KD mice after 20 weeks compared to WT mice. Moreover, the Clock gene was found to be significantly downregulated in WT MASLD mice. The Clock gene was shown to regulate the expression of lipophagy-related proteins (LC3B, P62, RAB7, and PLIN2) in vivo and in vitro. Knockdown of Clock was found to inhibit lipophagy resulting in increased accumulation of lipid droplets in the mouse liver and AML12 cells. Interestingly, the CLOCK protein was shown to interact with P62. However, knockdown of the Clock gene did not promote transcription of the P62 gene but suppressed degradation of the P62 protein during lipophagy in AML12 cells. The hepatic Clock gene regulates lipophagy and affects lipid droplet deposition in liver cells, and thus plays a critical role in the development of MASLD induced by a Western diet.

摘要

代谢功能障碍相关脂肪性肝炎(MASLD)在全球范围内患病率的增加与昼夜节律钟的慢性紊乱密切相关。在此,我们研究核心昼夜节律基因Clock在MASLD发病机制中的作用。给野生型(WT)小鼠和肝脏特异性Clock基因敲低(Clock-KD)小鼠喂食西式饮食20周以诱导MASLD。通过用游离脂肪酸处理AML12细胞建立细胞MASLD模型,并在用Clock siRNA转染后检查Clock基因敲低的影响。与WT小鼠相比,20周后,喂食西式饮食而非正常普通饮食的Clock-KD小鼠肝脏中观察到脂质沉积增加以及更严重的脂肪性肝炎和纤维化。此外,发现Clock基因在WT MASLD小鼠中显著下调。在体内和体外均显示Clock基因调节自噬相关蛋白(LC3B、P62、RAB7和PLIN2)的表达。发现敲低Clock可抑制自噬,导致小鼠肝脏和AML12细胞中脂滴积累增加。有趣的是,显示CLOCK蛋白与P62相互作用。然而,敲低Clock基因并未促进P62基因的转录,但在AML12细胞自噬过程中抑制了P62蛋白的降解。肝脏Clock基因调节自噬并影响肝细胞中的脂滴沉积,因此在西式饮食诱导的MASLD发展中起关键作用。

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