Activation of mTORC1 by Free Fatty Acids Suppresses LAMP2 and Autophagy Function via ER Stress in Alcohol-Related Liver Disease

被引:16
作者
Guo, Wei [1 ]
Zhong, Wei [1 ,2 ]
Hao, Liuyi [1 ]
Sun, Xinguo [1 ]
Zhou, Zhanxiang [1 ,2 ]
机构
[1] Univ North Carolina Greensboro, Ctr Translat Biomed Res, North Carolina Res Campus, Kannapolis, NC 28081 USA
[2] Univ North Carolina Greensboro, Dept Nutr, North Carolina Res Campus, Kannapolis, NC 28081 USA
基金
美国国家卫生研究院;
关键词
mTORC1; free fatty acid; ER stress; LAMP2; inflammation; alcohol-related liver disease; ENDOPLASMIC-RETICULUM STRESS; GROWTH; METABOLISM; APOPTOSIS; CANCER; TARGET;
D O I
10.3390/cells10102730
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and liver injury. The present study aimed to investigate if mechanistic target of rapamycin complex 1 (mTORC1) plays a role in FFA-induced organelle dysfunction, thereby contributing to the development of ALD. Cell studies were conducted to define the causal role and underlying mechanism of FFA-activated mTORC1 signaling in hepatocellular cell injury. C57BL/6J wild-type mice were subjected to chronic alcohol feeding with or without rapamycin to inhibit mTORC1 activation. We revealed that palmitic acid (PA)-induced ER stress and suppression of LAMP2 and autophagy flux were mTORC1-dependent as rapamycin reversed such deleterious effects. C/EBP homologous protein (CHOP) was downstream of ATF4 which partially modulated LAMP2. Supplementation with rapamycin to alcohol-fed mice attenuated mTORC1 activation and ER stress, restored LAMP2 protein, and improved autophagy, leading to amelioration of alcohol-induced liver injury. Induction of mTORC1 signaling and CHOP were also detected in the liver of patients with severe alcoholic hepatitis. This study demonstrates that hepatic FFAs play a crucial role in the pathogenesis of ALD by activating mTORC1 signaling, thereby inducing ER stress and suppressing LAMP2-autophagy flux pathway, which represents an important mechanism of FFA-induced hepatocellular injury.
引用
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页数:13
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