A patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis
Abstract Only ~20% of heavy drinkers develop alcohol cirrhosis (AC). While differences in metabolism, inflammation, signaling, microbiome signatures and genetic variations have been tied to the pathogenesis of AC, the key underlying mechanisms for this interindividual variability, remain to be fully...
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Nature Portfolio
2024-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-47085-y |
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| author | Bani Mukhopadhyay Cheryl Marietta Pei-Hong Shen Abdul Oiseni Faridoddin Mirshahi Maria Mazzu Colin Hodgkinson Eli Winkler Qiaoping Yuan Daniel Miranda George Kunos Arun J. Sanyal David Goldman |
| author_facet | Bani Mukhopadhyay Cheryl Marietta Pei-Hong Shen Abdul Oiseni Faridoddin Mirshahi Maria Mazzu Colin Hodgkinson Eli Winkler Qiaoping Yuan Daniel Miranda George Kunos Arun J. Sanyal David Goldman |
| author_sort | Bani Mukhopadhyay |
| collection | DOAJ |
| description | Abstract Only ~20% of heavy drinkers develop alcohol cirrhosis (AC). While differences in metabolism, inflammation, signaling, microbiome signatures and genetic variations have been tied to the pathogenesis of AC, the key underlying mechanisms for this interindividual variability, remain to be fully elucidated. Induced pluripotent stem cell-derived hepatocytes (iHLCs) from patients with AC and healthy controls differ transcriptomically, bioenergetically and histologically. They include a greater number of lipid droplets (LDs) and LD-associated mitochondria compared to control cells. These pre-pathologic indicators are effectively reversed by Aramchol, an inhibitor of stearoyl-CoA desaturase. Bioenergetically, AC iHLCs have lower spare capacity, slower ATP production and their mitochondrial fuel flexibility towards fatty acids and glutamate is weakened. MARC1 and PNPLA3, genes implicated by GWAS in alcohol cirrhosis, show to correlate with lipid droplet-associated and mitochondria-mediated oxidative damage in AC iHLCs. Knockdown of PNPLA3 expression exacerbates mitochondrial deficits and leads to lipid droplets alterations. These findings suggest that differences in mitochondrial bioenergetics and lipid droplet formation are intrinsic to AC hepatocytes and can play a role in its pathogenesis. |
| format | Article |
| id | doaj-art-5e94a80be9ff4499a96a3e21c2c7338e |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-5e94a80be9ff4499a96a3e21c2c7338e2025-02-02T12:30:58ZengNature PortfolioNature Communications2041-17232024-05-0115111910.1038/s41467-024-47085-yA patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesisBani Mukhopadhyay0Cheryl Marietta1Pei-Hong Shen2Abdul Oiseni3Faridoddin Mirshahi4Maria Mazzu5Colin Hodgkinson6Eli Winkler7Qiaoping Yuan8Daniel Miranda9George Kunos10Arun J. Sanyal11David Goldman12Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIHLaboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIHLaboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIHDivision of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of MedicineDivision of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of MedicineLaboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIHLaboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIHLaboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIHLaboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIHAivia Machine Learning Team, Leica Microsystems, IncLaboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, NIHDivision of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of MedicineLaboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIHAbstract Only ~20% of heavy drinkers develop alcohol cirrhosis (AC). While differences in metabolism, inflammation, signaling, microbiome signatures and genetic variations have been tied to the pathogenesis of AC, the key underlying mechanisms for this interindividual variability, remain to be fully elucidated. Induced pluripotent stem cell-derived hepatocytes (iHLCs) from patients with AC and healthy controls differ transcriptomically, bioenergetically and histologically. They include a greater number of lipid droplets (LDs) and LD-associated mitochondria compared to control cells. These pre-pathologic indicators are effectively reversed by Aramchol, an inhibitor of stearoyl-CoA desaturase. Bioenergetically, AC iHLCs have lower spare capacity, slower ATP production and their mitochondrial fuel flexibility towards fatty acids and glutamate is weakened. MARC1 and PNPLA3, genes implicated by GWAS in alcohol cirrhosis, show to correlate with lipid droplet-associated and mitochondria-mediated oxidative damage in AC iHLCs. Knockdown of PNPLA3 expression exacerbates mitochondrial deficits and leads to lipid droplets alterations. These findings suggest that differences in mitochondrial bioenergetics and lipid droplet formation are intrinsic to AC hepatocytes and can play a role in its pathogenesis.https://doi.org/10.1038/s41467-024-47085-y |
| spellingShingle | Bani Mukhopadhyay Cheryl Marietta Pei-Hong Shen Abdul Oiseni Faridoddin Mirshahi Maria Mazzu Colin Hodgkinson Eli Winkler Qiaoping Yuan Daniel Miranda George Kunos Arun J. Sanyal David Goldman A patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis Nature Communications |
| title | A patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis |
| title_full | A patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis |
| title_fullStr | A patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis |
| title_full_unstemmed | A patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis |
| title_short | A patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis |
| title_sort | patient based ipsc derived hepatocyte model of alcohol associated cirrhosis reveals bioenergetic insights into disease pathogenesis |
| url | https://doi.org/10.1038/s41467-024-47085-y |
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