Critical Role of TFEB-Mediated Lysosomal Biogenesis in Alcohol-Induced Pancreatitis in Mice and HumansSummary
Background & Aims: Alcohol abuse is the major cause of experimental and human pancreatitis but the molecular mechanisms remain largely unknown. We investigated the role of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, in the pathogenesis of alcoholic pancreatiti...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X2030014X |
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| author | Shaogui Wang Hong-Min Ni Xiaojuan Chao Xiaowen Ma Thomas Kolodecik Robert De Lisle Andrew Ballabio Pal Pacher Wen-Xing Ding |
| author_facet | Shaogui Wang Hong-Min Ni Xiaojuan Chao Xiaowen Ma Thomas Kolodecik Robert De Lisle Andrew Ballabio Pal Pacher Wen-Xing Ding |
| author_sort | Shaogui Wang |
| collection | DOAJ |
| description | Background & Aims: Alcohol abuse is the major cause of experimental and human pancreatitis but the molecular mechanisms remain largely unknown. We investigated the role of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, in the pathogenesis of alcoholic pancreatitis. Methods: Using a chronic plus acute alcohol binge (referred to as Gao-binge) mouse model, we analyzed pancreas injury, autophagic flux, zymogen granule removal, TFEB nuclear translocation and lysosomal biogenesis in GFP-LC3 transgenic mice, acinar cell-specific Atg5 knockout (KO) and TFEB KO mice as well as their matched wild type mice. Results: We found that Gao-binge alcohol induced typical features of pancreatitis in mice with increased serum amylase and lipase activities, pancreatic edema, infiltration of inflammatory cells, accumulation of zymogen granules (ZGs) and expression of inflammatory cytokines. While Gao-binge alcohol increased the number of autophagosomes, it also concurrently inhibited TFEB nuclear translocation and TFEB-mediated lysosomal biogenesis resulting in insufficient autophagy. Acinar cell-specific Atg5 KO and acinar cell-specific TFEB KO mice developed severe inflammatory and fibrotic pancreatitis in both Gao-binge alcohol and control diet-fed mice. In contrast, TFEB overexpression inhibited alcohol-induced pancreatic edema, accumulation of zymogen granules and serum amylase and lipase activities. In line with our findings in mice, decreased LAMP1 and TFEB nuclear staining were also observed in human alcoholic pancreatitis tissues. Conclusions: our results indicate that TFEB plays a critical role in maintaining pancreatic acinar cell homeostasis. Impairment of TFEB-mediated lysosomal biogenesis by alcohol may lead to insufficient autophagy and promote alcohol-induced pancreatitis. |
| first_indexed | 2024-12-11T22:12:42Z |
| format | Article |
| id | doaj.art-7c062c72fdbf45cc99a47741f74c977f |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-11T22:12:42Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-7c062c72fdbf45cc99a47741f74c977f2022-12-22T00:48:42ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2020-01-011015981Critical Role of TFEB-Mediated Lysosomal Biogenesis in Alcohol-Induced Pancreatitis in Mice and HumansSummaryShaogui Wang0Hong-Min Ni1Xiaojuan Chao2Xiaowen Ma3Thomas Kolodecik4Robert De Lisle5Andrew Ballabio6Pal Pacher7Wen-Xing Ding8Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KansasDepartment of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KansasDepartment of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KansasDepartment of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KansasDigestive Diseases Section, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut; West Haven VA Medical Center, VA Connecticut Health System, West Haven, ConnecticutDepartment of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KansasTelethon Institute of Genetics and Medicine, Telethon Institute of Genetics and Medicine, Pozzuoli, Italy; Medical Genetics, Department of Translational Medicine, Federico II University, Naples, Italy; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TexasLaboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MarylandDepartment of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas; Correspondence Address reprint requests to: Wen-Xing Ding, PhD, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160; fax: (913) 588-7501.Background & Aims: Alcohol abuse is the major cause of experimental and human pancreatitis but the molecular mechanisms remain largely unknown. We investigated the role of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, in the pathogenesis of alcoholic pancreatitis. Methods: Using a chronic plus acute alcohol binge (referred to as Gao-binge) mouse model, we analyzed pancreas injury, autophagic flux, zymogen granule removal, TFEB nuclear translocation and lysosomal biogenesis in GFP-LC3 transgenic mice, acinar cell-specific Atg5 knockout (KO) and TFEB KO mice as well as their matched wild type mice. Results: We found that Gao-binge alcohol induced typical features of pancreatitis in mice with increased serum amylase and lipase activities, pancreatic edema, infiltration of inflammatory cells, accumulation of zymogen granules (ZGs) and expression of inflammatory cytokines. While Gao-binge alcohol increased the number of autophagosomes, it also concurrently inhibited TFEB nuclear translocation and TFEB-mediated lysosomal biogenesis resulting in insufficient autophagy. Acinar cell-specific Atg5 KO and acinar cell-specific TFEB KO mice developed severe inflammatory and fibrotic pancreatitis in both Gao-binge alcohol and control diet-fed mice. In contrast, TFEB overexpression inhibited alcohol-induced pancreatic edema, accumulation of zymogen granules and serum amylase and lipase activities. In line with our findings in mice, decreased LAMP1 and TFEB nuclear staining were also observed in human alcoholic pancreatitis tissues. Conclusions: our results indicate that TFEB plays a critical role in maintaining pancreatic acinar cell homeostasis. Impairment of TFEB-mediated lysosomal biogenesis by alcohol may lead to insufficient autophagy and promote alcohol-induced pancreatitis.http://www.sciencedirect.com/science/article/pii/S2352345X2030014XAutophagyLysosomeInflammationTissue InjuryZymogen |
| spellingShingle | Shaogui Wang Hong-Min Ni Xiaojuan Chao Xiaowen Ma Thomas Kolodecik Robert De Lisle Andrew Ballabio Pal Pacher Wen-Xing Ding Critical Role of TFEB-Mediated Lysosomal Biogenesis in Alcohol-Induced Pancreatitis in Mice and HumansSummary Cellular and Molecular Gastroenterology and Hepatology Autophagy Lysosome Inflammation Tissue Injury Zymogen |
| title | Critical Role of TFEB-Mediated Lysosomal Biogenesis in Alcohol-Induced Pancreatitis in Mice and HumansSummary |
| title_full | Critical Role of TFEB-Mediated Lysosomal Biogenesis in Alcohol-Induced Pancreatitis in Mice and HumansSummary |
| title_fullStr | Critical Role of TFEB-Mediated Lysosomal Biogenesis in Alcohol-Induced Pancreatitis in Mice and HumansSummary |
| title_full_unstemmed | Critical Role of TFEB-Mediated Lysosomal Biogenesis in Alcohol-Induced Pancreatitis in Mice and HumansSummary |
| title_short | Critical Role of TFEB-Mediated Lysosomal Biogenesis in Alcohol-Induced Pancreatitis in Mice and HumansSummary |
| title_sort | critical role of tfeb mediated lysosomal biogenesis in alcohol induced pancreatitis in mice and humanssummary |
| topic | Autophagy Lysosome Inflammation Tissue Injury Zymogen |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X2030014X |
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