DNA 6mA Demethylase ALKBH1 Orchestrates Fatty Acid Metabolism and Suppresses Diet-Induced Hepatic SteatosisSummary
Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity and mortality whereas the pathogenic mechanism remains largely elusive. DNA N6-methyladenosine (6mA) modification is a recently identified epigenetic mark indicative of transcription in eu...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X22001928 |
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| author | Liping Luo Ya Liu Paul Nizigiyimana Mingsheng Ye Ye Xiao Qi Guo Tian Su Xianghang Luo Yan Huang Haiyan Zhou |
| author_facet | Liping Luo Ya Liu Paul Nizigiyimana Mingsheng Ye Ye Xiao Qi Guo Tian Su Xianghang Luo Yan Huang Haiyan Zhou |
| author_sort | Liping Luo |
| collection | DOAJ |
| description | Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity and mortality whereas the pathogenic mechanism remains largely elusive. DNA N6-methyladenosine (6mA) modification is a recently identified epigenetic mark indicative of transcription in eukaryotic genomes. Here, we aimed to investigate the role and mechanism of DNA 6mA modification in NAFLD progression. Methods: Dot blot and immunohistochemistry were used to detect DNA 6mA levels. Liver-specific AlkB homolog 1 (ALKBH1)-knockout mice and mice with ALKBH1 overexpression in liver were subjected to a high-fat diet or methionine choline-deficient diet to evaluate the critical role of ALKBH1-demethylated DNA 6mA modification in the pathogenesis of hepatic steatosis during NAFLD. RNA sequencing and chromatin immunoprecipitation sequencing were performed to investigate molecular mechanisms underlying this process. Results: The DNA 6mA level was increased significantly with hepatic steatosis, while ALKBH1 expression was down-regulated markedly in both mouse and human fatty liver. Deletion of ALKBH1 in hepatocytes increased genomic 6mA levels and accelerated diet-induced hepatic steatosis and metabolic dysfunction. Comprehensive analyses of transcriptome and chromatin immunoprecipitation sequencing data indicated that ALKBH1 directly bound to and exclusively demethylated 6mA levels of genes involved in fatty acid uptake and lipogenesis, leading to reduced hepatic lipid accumulation. Importantly, ALKBH1 overexpression was sufficient to suppress lipid uptake and synthesis, and alleviated diet-induced hepatic steatosis and insulin resistance. Conclusions: Our findings show an indispensable role of ALKBH1 as an epigenetic suppressor of DNA 6mA in hepatic fatty acid metabolism and offer a potential therapeutic target for NAFLD treatment. |
| first_indexed | 2024-04-13T23:42:05Z |
| format | Article |
| id | doaj.art-e5d92665d7564566b4bacf20d5ea9e45 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-04-13T23:42:05Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
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| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-e5d92665d7564566b4bacf20d5ea9e452022-12-22T02:24:29ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2022-01-0114612131233DNA 6mA Demethylase ALKBH1 Orchestrates Fatty Acid Metabolism and Suppresses Diet-Induced Hepatic SteatosisSummaryLiping Luo0Ya Liu1Paul Nizigiyimana2Mingsheng Ye3Ye Xiao4Qi Guo5Tian Su6Xianghang Luo7Yan Huang8Haiyan Zhou9Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, ChinaDepartment of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, ChinaDepartment of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China; Correspondence Address correspondence to: Haiyan Zhou, PhD, Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, No 87, Xiangya Road, Changsha, Hunan Province 410008, China.Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity and mortality whereas the pathogenic mechanism remains largely elusive. DNA N6-methyladenosine (6mA) modification is a recently identified epigenetic mark indicative of transcription in eukaryotic genomes. Here, we aimed to investigate the role and mechanism of DNA 6mA modification in NAFLD progression. Methods: Dot blot and immunohistochemistry were used to detect DNA 6mA levels. Liver-specific AlkB homolog 1 (ALKBH1)-knockout mice and mice with ALKBH1 overexpression in liver were subjected to a high-fat diet or methionine choline-deficient diet to evaluate the critical role of ALKBH1-demethylated DNA 6mA modification in the pathogenesis of hepatic steatosis during NAFLD. RNA sequencing and chromatin immunoprecipitation sequencing were performed to investigate molecular mechanisms underlying this process. Results: The DNA 6mA level was increased significantly with hepatic steatosis, while ALKBH1 expression was down-regulated markedly in both mouse and human fatty liver. Deletion of ALKBH1 in hepatocytes increased genomic 6mA levels and accelerated diet-induced hepatic steatosis and metabolic dysfunction. Comprehensive analyses of transcriptome and chromatin immunoprecipitation sequencing data indicated that ALKBH1 directly bound to and exclusively demethylated 6mA levels of genes involved in fatty acid uptake and lipogenesis, leading to reduced hepatic lipid accumulation. Importantly, ALKBH1 overexpression was sufficient to suppress lipid uptake and synthesis, and alleviated diet-induced hepatic steatosis and insulin resistance. Conclusions: Our findings show an indispensable role of ALKBH1 as an epigenetic suppressor of DNA 6mA in hepatic fatty acid metabolism and offer a potential therapeutic target for NAFLD treatment.http://www.sciencedirect.com/science/article/pii/S2352345X22001928DNA 6mAALKBH1DemethylationFatty LiverLipid Metabolism |
| spellingShingle | Liping Luo Ya Liu Paul Nizigiyimana Mingsheng Ye Ye Xiao Qi Guo Tian Su Xianghang Luo Yan Huang Haiyan Zhou DNA 6mA Demethylase ALKBH1 Orchestrates Fatty Acid Metabolism and Suppresses Diet-Induced Hepatic SteatosisSummary Cellular and Molecular Gastroenterology and Hepatology DNA 6mA ALKBH1 Demethylation Fatty Liver Lipid Metabolism |
| title | DNA 6mA Demethylase ALKBH1 Orchestrates Fatty Acid Metabolism and Suppresses Diet-Induced Hepatic SteatosisSummary |
| title_full | DNA 6mA Demethylase ALKBH1 Orchestrates Fatty Acid Metabolism and Suppresses Diet-Induced Hepatic SteatosisSummary |
| title_fullStr | DNA 6mA Demethylase ALKBH1 Orchestrates Fatty Acid Metabolism and Suppresses Diet-Induced Hepatic SteatosisSummary |
| title_full_unstemmed | DNA 6mA Demethylase ALKBH1 Orchestrates Fatty Acid Metabolism and Suppresses Diet-Induced Hepatic SteatosisSummary |
| title_short | DNA 6mA Demethylase ALKBH1 Orchestrates Fatty Acid Metabolism and Suppresses Diet-Induced Hepatic SteatosisSummary |
| title_sort | dna 6ma demethylase alkbh1 orchestrates fatty acid metabolism and suppresses diet induced hepatic steatosissummary |
| topic | DNA 6mA ALKBH1 Demethylation Fatty Liver Lipid Metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X22001928 |
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