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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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X21001430 |
| _version_ | 1818929943233429504 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-20T03:52:50Z |
| format | Article |
| id | doaj.art-9a339ec9927c4e4e9e9dcfcd791d6c62 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-20T03:52:50Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-9a339ec9927c4e4e9e9dcfcd791d6c622022-12-21T19:54:26ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2021-01-0112515991615Fatty Acids Inhibit LAMP2-Mediated Autophagy Flux via Activating ER Stress Pathway in Alcohol-Related Liver DiseaseSummaryWei Guo0Wei Zhong1Liuyi Hao2Haibo Dong3Xinguo Sun4Ruichao Yue5Tianjiao Li6Zhanxiang Zhou7Center for Translational Biomedical Research, Kannapolis, North CarolinaCenter for Translational Biomedical Research, Kannapolis, North Carolina; Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North CarolinaCenter for Translational Biomedical Research, Kannapolis, North CarolinaCenter for Translational Biomedical Research, Kannapolis, North CarolinaCenter for Translational Biomedical Research, Kannapolis, North CarolinaCenter for Translational Biomedical Research, Kannapolis, North CarolinaDepartment of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North CarolinaCenter for Translational Biomedical Research, Kannapolis, North Carolina; Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, North Carolina; Correspondence Address correspondence to: Zhanxiang Zhou, PhD, Center for Translational Biomedical Research, University of North Carolina at Greensboro, 600 Laureate Way, Suite 2203, Kannapolis, North Carolina 28081.fax: (704) 250-5809.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.http://www.sciencedirect.com/science/article/pii/S2352345X21001430Free Fatty AcidDGAT1LipotoxicityAutophagyAlcohol-Induced Liver Injury |
| spellingShingle | 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 Cellular and Molecular Gastroenterology and Hepatology Free Fatty Acid DGAT1 Lipotoxicity Autophagy Alcohol-Induced Liver Injury |
| title | 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_short | 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 |
| topic | Free Fatty Acid DGAT1 Lipotoxicity Autophagy Alcohol-Induced Liver Injury |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X21001430 |
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