Augmenter of Liver Regeneration Crotonylation Assists in Mitochondria-ER Contact to Alleviate Hepatic SteatosisSummary
Background & Aims: Crotonylation (Kcr), a newly identified post-translation modification (PTM), has been confirmed to be involved in diverse biological processes and human diseases as well. Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a serious threat to people’s he...
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Elsevier
2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X24001917 |
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| author | Xiao-lin Wang Jia-hao He Ping Xie Yuan Wu Ling-yue Dong Wei An |
| author_facet | Xiao-lin Wang Jia-hao He Ping Xie Yuan Wu Ling-yue Dong Wei An |
| author_sort | Xiao-lin Wang |
| collection | DOAJ |
| description | Background & Aims: Crotonylation (Kcr), a newly identified post-translation modification (PTM), has been confirmed to be involved in diverse biological processes and human diseases as well. Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a serious threat to people’s health. Augmenter of liver regeneration (ALR) is an important liver regulatory protein, and the insufficiency of ALR expression is reported to accelerate liver steatosis progression to liver fibrosis or even hepatic carcinoma (HCC). However, the connection between dysregulated ALR crotonylation and MASLD pathogenesis remains largely unknown. Methods: Steatotic liver samples from human and Western diet (WD)-fed mice were employed for detecting Kcr levels. Mitochondrial function and mitochondria-ER interaction (MAM) relevant to ALR-Kcr modification was evaluated for hepatocyte lipid metabolism both in in vivo and in vitro experiments. Results: Global protein crotonylation (Kcr) as well as ALR-Kcr was significantly decreased in liver samples of patients with MASLD and WD mice. Histone deacetylase1/2 (HDAC1/2) and lysine acetyltransferase 8 (KAT8) were identified responsible for regulation of ALR-Kcr, which takes place at lysine 78 (K78). The decrease of ALR crotonylation might be related to the imbalance between HDAC1/2 and KAT8 expression, inhibited its interaction with MFN2, expanding MAM distance and impairing mitochondrial lipid metabolism, and consequently deteriorating hepatic steatosis. Conclusions: The insufficient ALR crotonylation might be a crucial mechanism contributing to the pathogenesis of MASLD. Keeping ALR crotonylation level would be beneficial for the prevention and treatment of MASLD. |
| format | Article |
| id | doaj-art-9f1cbba17e564c03aa5149ffdf779ef8 |
| institution | Kabale University |
| issn | 2352-345X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj-art-9f1cbba17e564c03aa5149ffdf779ef82025-01-19T06:26:11ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2025-01-01193101436Augmenter of Liver Regeneration Crotonylation Assists in Mitochondria-ER Contact to Alleviate Hepatic SteatosisSummaryXiao-lin Wang0Jia-hao He1Ping Xie2Yuan Wu3Ling-yue Dong4Wei An5Department of Cell Biology and the Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, People's Republic of ChinaDepartment of Cell Biology and the Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, People's Republic of ChinaDepartment of Cell Biology and the Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, People's Republic of ChinaDepartment of Cell Biology and the Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, People's Republic of ChinaDepartment of Cell Biology and the Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, People's Republic of ChinaCorrespondence Address correspondence to: Dr Wei An, Department of Cell Biology, 10 You An Men Wai, FeingTai District, Beijing 100069, China.; Department of Cell Biology and the Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, People's Republic of ChinaBackground & Aims: Crotonylation (Kcr), a newly identified post-translation modification (PTM), has been confirmed to be involved in diverse biological processes and human diseases as well. Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a serious threat to people’s health. Augmenter of liver regeneration (ALR) is an important liver regulatory protein, and the insufficiency of ALR expression is reported to accelerate liver steatosis progression to liver fibrosis or even hepatic carcinoma (HCC). However, the connection between dysregulated ALR crotonylation and MASLD pathogenesis remains largely unknown. Methods: Steatotic liver samples from human and Western diet (WD)-fed mice were employed for detecting Kcr levels. Mitochondrial function and mitochondria-ER interaction (MAM) relevant to ALR-Kcr modification was evaluated for hepatocyte lipid metabolism both in in vivo and in vitro experiments. Results: Global protein crotonylation (Kcr) as well as ALR-Kcr was significantly decreased in liver samples of patients with MASLD and WD mice. Histone deacetylase1/2 (HDAC1/2) and lysine acetyltransferase 8 (KAT8) were identified responsible for regulation of ALR-Kcr, which takes place at lysine 78 (K78). The decrease of ALR crotonylation might be related to the imbalance between HDAC1/2 and KAT8 expression, inhibited its interaction with MFN2, expanding MAM distance and impairing mitochondrial lipid metabolism, and consequently deteriorating hepatic steatosis. Conclusions: The insufficient ALR crotonylation might be a crucial mechanism contributing to the pathogenesis of MASLD. Keeping ALR crotonylation level would be beneficial for the prevention and treatment of MASLD.http://www.sciencedirect.com/science/article/pii/S2352345X24001917Augmenter of Liver RegenerationCrotonylationMitochondria-associated MembraneMetabolic Dysfunction-associated Steatotic Liver Disease |
| spellingShingle | Xiao-lin Wang Jia-hao He Ping Xie Yuan Wu Ling-yue Dong Wei An Augmenter of Liver Regeneration Crotonylation Assists in Mitochondria-ER Contact to Alleviate Hepatic SteatosisSummary Cellular and Molecular Gastroenterology and Hepatology Augmenter of Liver Regeneration Crotonylation Mitochondria-associated Membrane Metabolic Dysfunction-associated Steatotic Liver Disease |
| title | Augmenter of Liver Regeneration Crotonylation Assists in Mitochondria-ER Contact to Alleviate Hepatic SteatosisSummary |
| title_full | Augmenter of Liver Regeneration Crotonylation Assists in Mitochondria-ER Contact to Alleviate Hepatic SteatosisSummary |
| title_fullStr | Augmenter of Liver Regeneration Crotonylation Assists in Mitochondria-ER Contact to Alleviate Hepatic SteatosisSummary |
| title_full_unstemmed | Augmenter of Liver Regeneration Crotonylation Assists in Mitochondria-ER Contact to Alleviate Hepatic SteatosisSummary |
| title_short | Augmenter of Liver Regeneration Crotonylation Assists in Mitochondria-ER Contact to Alleviate Hepatic SteatosisSummary |
| title_sort | augmenter of liver regeneration crotonylation assists in mitochondria er contact to alleviate hepatic steatosissummary |
| topic | Augmenter of Liver Regeneration Crotonylation Mitochondria-associated Membrane Metabolic Dysfunction-associated Steatotic Liver Disease |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X24001917 |
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