TET1 promotes fatty acid oxidation and inhibits NAFLD progression by hydroxymethylation of PPARα promoter
Abstract Background As a lipid metabolic disorder, non-alcoholic fatty liver disease (NAFLD) is an important cause of cirrhosis and hepatocellular carcinoma, with no effective drug up to date. Previous studies have demonstrated increased methylation levels of key genes in NAFLD, suggesting that hydr...
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| Format: | Article |
| Language: | English |
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BMC
2020-06-01
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| Series: | Nutrition & Metabolism |
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| Online Access: | http://link.springer.com/article/10.1186/s12986-020-00466-8 |
| _version_ | 1819015713168293888 |
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| author | Jingjie Wang Yitong Zhang Qin Zhuo Yujen Tseng Jiucun Wang Yanyun Ma Jun Zhang Jie Liu |
| author_facet | Jingjie Wang Yitong Zhang Qin Zhuo Yujen Tseng Jiucun Wang Yanyun Ma Jun Zhang Jie Liu |
| author_sort | Jingjie Wang |
| collection | DOAJ |
| description | Abstract Background As a lipid metabolic disorder, non-alcoholic fatty liver disease (NAFLD) is an important cause of cirrhosis and hepatocellular carcinoma, with no effective drug up to date. Previous studies have demonstrated increased methylation levels of key genes in NAFLD, suggesting that hydroxymethylation, a key step in demethylation, may be a possible strategy to reverse NAFLD. TET1 is well known as a key hydroxymethylase, however, its role and mechanism in NAFLD remains unclear. Methods In this study, we utilized TET1 knockout mice, fed with high-fat diet. Furthermore, by ChIP and hMeDIP. TET1 knockdown L02 and HepG2 cell lines. Results Their degree of liver steatosis was more severe than that of wild-type mice, suggesting that TET1 had a significant protective effect against NAFLD. We further found that PPARα, a key regulator of fatty acid oxidation, and its downstream key enzymes ACOX1 and CPT1A, as well as the fatty acid oxidation product β-HB were significantly decreased in TET1 knockout mice. While the key genes for fatty acid synthesis and uptake were not significantly changed, suggesting that TET1 inhibits NAFLD by promoting fatty acid oxidation via PPARα pathway. TET1 was confirmed to directly bind to the promoter of PPARα and elevate its hydroxymethylation level. Conclusions This study is the first to show that TET1 can activate PPARα, promote fatty acid oxidation and inhibit NAFLD progression by hydroxymethylation of PPARα promoter, which may be a new strategy to reverse NAFLD. |
| first_indexed | 2024-12-21T02:36:06Z |
| format | Article |
| id | doaj.art-3be2a09f2b774ea0a77ac8d6e3ce8470 |
| institution | Directory Open Access Journal |
| issn | 1743-7075 |
| language | English |
| last_indexed | 2024-12-21T02:36:06Z |
| publishDate | 2020-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Nutrition & Metabolism |
| spelling | doaj.art-3be2a09f2b774ea0a77ac8d6e3ce84702022-12-21T19:18:47ZengBMCNutrition & Metabolism1743-70752020-06-0117111110.1186/s12986-020-00466-8TET1 promotes fatty acid oxidation and inhibits NAFLD progression by hydroxymethylation of PPARα promoterJingjie Wang0Yitong Zhang1Qin Zhuo2Yujen Tseng3Jiucun Wang4Yanyun Ma5Jun Zhang6Jie Liu7Department of Digestive Diseases of Huashan Hospital and Institutes of Biomedical Sciences, Fudan UniversityDepartment of Digestive Diseases of Huashan Hospital and Institutes of Biomedical Sciences, Fudan UniversityDepartment of Digestive Diseases of Huashan Hospital and Institutes of Biomedical Sciences, Fudan UniversityDepartment of Digestive Diseases of Huashan Hospital and Institutes of Biomedical Sciences, Fudan UniversityState Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan UniversityState Key Laboratory of Genetic Engineering, Human Phenome Institute, Fudan UniversityDepartment of Digestive Diseases of Huashan Hospital and Institutes of Biomedical Sciences, Fudan UniversityDepartment of Digestive Diseases of Huashan Hospital and Institutes of Biomedical Sciences, Fudan UniversityAbstract Background As a lipid metabolic disorder, non-alcoholic fatty liver disease (NAFLD) is an important cause of cirrhosis and hepatocellular carcinoma, with no effective drug up to date. Previous studies have demonstrated increased methylation levels of key genes in NAFLD, suggesting that hydroxymethylation, a key step in demethylation, may be a possible strategy to reverse NAFLD. TET1 is well known as a key hydroxymethylase, however, its role and mechanism in NAFLD remains unclear. Methods In this study, we utilized TET1 knockout mice, fed with high-fat diet. Furthermore, by ChIP and hMeDIP. TET1 knockdown L02 and HepG2 cell lines. Results Their degree of liver steatosis was more severe than that of wild-type mice, suggesting that TET1 had a significant protective effect against NAFLD. We further found that PPARα, a key regulator of fatty acid oxidation, and its downstream key enzymes ACOX1 and CPT1A, as well as the fatty acid oxidation product β-HB were significantly decreased in TET1 knockout mice. While the key genes for fatty acid synthesis and uptake were not significantly changed, suggesting that TET1 inhibits NAFLD by promoting fatty acid oxidation via PPARα pathway. TET1 was confirmed to directly bind to the promoter of PPARα and elevate its hydroxymethylation level. Conclusions This study is the first to show that TET1 can activate PPARα, promote fatty acid oxidation and inhibit NAFLD progression by hydroxymethylation of PPARα promoter, which may be a new strategy to reverse NAFLD.http://link.springer.com/article/10.1186/s12986-020-00466-8TET1NAFLDPPARαFatty acid oxidationHydroxymethylation |
| spellingShingle | Jingjie Wang Yitong Zhang Qin Zhuo Yujen Tseng Jiucun Wang Yanyun Ma Jun Zhang Jie Liu TET1 promotes fatty acid oxidation and inhibits NAFLD progression by hydroxymethylation of PPARα promoter Nutrition & Metabolism TET1 NAFLD PPARα Fatty acid oxidation Hydroxymethylation |
| title | TET1 promotes fatty acid oxidation and inhibits NAFLD progression by hydroxymethylation of PPARα promoter |
| title_full | TET1 promotes fatty acid oxidation and inhibits NAFLD progression by hydroxymethylation of PPARα promoter |
| title_fullStr | TET1 promotes fatty acid oxidation and inhibits NAFLD progression by hydroxymethylation of PPARα promoter |
| title_full_unstemmed | TET1 promotes fatty acid oxidation and inhibits NAFLD progression by hydroxymethylation of PPARα promoter |
| title_short | TET1 promotes fatty acid oxidation and inhibits NAFLD progression by hydroxymethylation of PPARα promoter |
| title_sort | tet1 promotes fatty acid oxidation and inhibits nafld progression by hydroxymethylation of pparα promoter |
| topic | TET1 NAFLD PPARα Fatty acid oxidation Hydroxymethylation |
| url | http://link.springer.com/article/10.1186/s12986-020-00466-8 |
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