Fatty Acids Inhibit LAMP2-Mediated Autophagy Flux via Activating ER Stress Pathway in Alcohol-Related Liver DiseaseSummary

Background & Aims: Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and triglyceride (TG)-enriched lipid droplets and cell death. The present study aimed to investigate how FFA or TG induces hepatocyte injury, thereby contributing to the...

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Autores principales:	Wei Guo, Wei Zhong, Liuyi Hao, Haibo Dong, Xinguo Sun, Ruichao Yue, Tianjiao Li, Zhanxiang Zhou
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Free Fatty Acid DGAT1 Lipotoxicity Autophagy Alcohol-Induced Liver Injury Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/9a339ec9927c4e4e9e9dcfcd791d6c62
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spelling	oai:doaj.org-article:9a339ec9927c4e4e9e9dcfcd791d6c622021-11-12T04:38:50ZFatty Acids Inhibit LAMP2-Mediated Autophagy Flux via Activating ER Stress Pathway in Alcohol-Related Liver DiseaseSummary2352-345X10.1016/j.jcmgh.2021.07.002https://doaj.org/article/9a339ec9927c4e4e9e9dcfcd791d6c622021-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001430https://doaj.org/toc/2352-345XBackground & Aims: Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and triglyceride (TG)-enriched lipid droplets and cell death. The present study aimed to investigate how FFA or TG induces hepatocyte injury, thereby contributing to the development of ALD. Methods: Hepatocyte-specific DGAT1 knockout (DGAT1Δhep) mice and lysosome-associated membrane protein 2 (LAMP2) overexpression mice were generated and subjected to chronic alcohol feeding. Cell studies were conducted to define the causal role and underlying mechanism of FFA-induced hepatocellular injury. Results: Hepatocyte-specific DGAT1 deletion exacerbated alcohol-induced liver injury by increasing lipid accumulation and endoplasmic reticulum (ER) stress, reducing LAMP2 protein levels, and impairing autophagy function. Cell studies revealed that FFAs, rather than TG, induced ER stress via ATF4 activation, which, in turn, down-regulated LAMP2, thereby impairing autophagy flux. LAMP2 overexpression in the liver restored autophagy function and ameliorated alcohol-induced liver injury in mice. Reducing hepatic FFAs by peroxisome proliferator-activated receptor α activation attenuated ER stress, restored LAMP2 protein levels, and improved autophagy flux. In addition, suppression of LAMP2 and autophagy function was also detected in the liver of patients with severe alcoholic hepatitis. Conclusions: This study demonstrates that accumulation of hepatic FFAs, rather than TG, plays a crucial role in the pathogenesis of ALD by suppressing LAMP2-autophagy flux pathway through ER stress signaling, which represents an important mechanism of FFA-induced hepatocellular injury in ALD.Wei GuoWei ZhongLiuyi HaoHaibo DongXinguo SunRuichao YueTianjiao LiZhanxiang ZhouElsevierarticleFree Fatty AcidDGAT1LipotoxicityAutophagyAlcohol-Induced Liver InjuryDiseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 5, Pp 1599-1615 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Free Fatty Acid DGAT1 Lipotoxicity Autophagy Alcohol-Induced Liver Injury Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Free Fatty Acid DGAT1 Lipotoxicity Autophagy Alcohol-Induced Liver Injury Diseases of the digestive system. Gastroenterology RC799-869 Wei Guo Wei Zhong Liuyi Hao Haibo Dong Xinguo Sun Ruichao Yue Tianjiao Li Zhanxiang Zhou Fatty Acids Inhibit LAMP2-Mediated Autophagy Flux via Activating ER Stress Pathway in Alcohol-Related Liver DiseaseSummary
description	Background & Aims: Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and triglyceride (TG)-enriched lipid droplets and cell death. The present study aimed to investigate how FFA or TG induces hepatocyte injury, thereby contributing to the development of ALD. Methods: Hepatocyte-specific DGAT1 knockout (DGAT1Δhep) mice and lysosome-associated membrane protein 2 (LAMP2) overexpression mice were generated and subjected to chronic alcohol feeding. Cell studies were conducted to define the causal role and underlying mechanism of FFA-induced hepatocellular injury. Results: Hepatocyte-specific DGAT1 deletion exacerbated alcohol-induced liver injury by increasing lipid accumulation and endoplasmic reticulum (ER) stress, reducing LAMP2 protein levels, and impairing autophagy function. Cell studies revealed that FFAs, rather than TG, induced ER stress via ATF4 activation, which, in turn, down-regulated LAMP2, thereby impairing autophagy flux. LAMP2 overexpression in the liver restored autophagy function and ameliorated alcohol-induced liver injury in mice. Reducing hepatic FFAs by peroxisome proliferator-activated receptor α activation attenuated ER stress, restored LAMP2 protein levels, and improved autophagy flux. In addition, suppression of LAMP2 and autophagy function was also detected in the liver of patients with severe alcoholic hepatitis. Conclusions: This study demonstrates that accumulation of hepatic FFAs, rather than TG, plays a crucial role in the pathogenesis of ALD by suppressing LAMP2-autophagy flux pathway through ER stress signaling, which represents an important mechanism of FFA-induced hepatocellular injury in ALD.
format	article
author	Wei Guo Wei Zhong Liuyi Hao Haibo Dong Xinguo Sun Ruichao Yue Tianjiao Li Zhanxiang Zhou
author_facet	Wei Guo Wei Zhong Liuyi Hao Haibo Dong Xinguo Sun Ruichao Yue Tianjiao Li Zhanxiang Zhou
author_sort	Wei Guo
title	Fatty Acids Inhibit LAMP2-Mediated Autophagy Flux via Activating ER Stress Pathway in Alcohol-Related Liver DiseaseSummary
title_short	Fatty Acids Inhibit LAMP2-Mediated Autophagy Flux via Activating ER Stress Pathway in Alcohol-Related Liver DiseaseSummary
title_full	Fatty Acids Inhibit LAMP2-Mediated Autophagy Flux via Activating ER Stress Pathway in Alcohol-Related Liver DiseaseSummary
title_fullStr	Fatty Acids Inhibit LAMP2-Mediated Autophagy Flux via Activating ER Stress Pathway in Alcohol-Related Liver DiseaseSummary
title_full_unstemmed	Fatty Acids Inhibit LAMP2-Mediated Autophagy Flux via Activating ER Stress Pathway in Alcohol-Related Liver DiseaseSummary
title_sort	fatty acids inhibit lamp2-mediated autophagy flux via activating er stress pathway in alcohol-related liver diseasesummary
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/9a339ec9927c4e4e9e9dcfcd791d6c62
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Fatty Acids Inhibit LAMP2-Mediated Autophagy Flux via Activating ER Stress Pathway in Alcohol-Related Liver DiseaseSummary

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