Metallothionein 1B attenuates inflammation and hepatic steatosis in MASH by inhibiting the AKT/PI3K pathway
Metabolic dysfunction–associated steatohepatitis (MASH) is a severe form of metabolic dysfunction–associated fatty liver disease metabolic dysfunction-associated steatohepatitis , characterized by hepatic steatosis, inflammation, and fibrosis. This study investigates the role and potential mechanism...
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Elsevier
2025-01-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227524002062 |
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| author | Canghai Guan Xinlei Zou Wujiang Shi Jianjun Gao Chengru Yang Yifei Ge Zhaoqiang Xu Shaowu Bi Xiangyu Zhong |
| author_facet | Canghai Guan Xinlei Zou Wujiang Shi Jianjun Gao Chengru Yang Yifei Ge Zhaoqiang Xu Shaowu Bi Xiangyu Zhong |
| author_sort | Canghai Guan |
| collection | DOAJ |
| description | Metabolic dysfunction–associated steatohepatitis (MASH) is a severe form of metabolic dysfunction–associated fatty liver disease metabolic dysfunction-associated steatohepatitis , characterized by hepatic steatosis, inflammation, and fibrosis. This study investigates the role and potential mechanisms of metallothionein 1B (MT1B) in MASH through bioinformatics analysis and experimental validation. quantitative reverse transcription PCR and Western blot analyses confirm that MT1B expression is significantly downregulated in liver tissues of MASH patients, in high-fat diet–induced mouse models, and in hepatocytes induced by FFAs. Further functional experiments show that upregulation of MT1B reduces intracellular triglycerides and total cholesterol levels, lipid droplet formation, and proinflammatory factors. In vivo experiments demonstrate that specific downregulation of hepatic MT1B expression via AAV8-shMT1B injection significantly increases triglyceride and total cholesterol levels, exacerbates lipid accumulation, and markedly elevates liver fibrosis and inflammatory factor expression. RNA-seq and bioinformatics analyses show that the AKT/PI3K pathway is significantly suppressed in MT1B-overexpressing cells. Further experiments indicate that AKT inhibition can reverse the lipid metabolism disorders and inflammatory responses caused by MT1B downregulation. Additionally, Zinc can promote the nuclear translocation of MTF1, leading to its binding to the MT1B promoter, thereby upregulating MT1B expression and ultimately mitigating MASH progression. These findings suggest that zinc-regulated MT1B plays a critical role in lipid metabolism and inflammatory responses by regulating the AKT/PI3K signaling pathway, influencing MASH progression. |
| format | Article |
| id | doaj-art-d200d09ba418408f92b9f47c17d37610 |
| institution | Kabale University |
| issn | 0022-2275 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-d200d09ba418408f92b9f47c17d376102025-01-30T05:12:36ZengElsevierJournal of Lipid Research0022-22752025-01-01661100701Metallothionein 1B attenuates inflammation and hepatic steatosis in MASH by inhibiting the AKT/PI3K pathwayCanghai Guan0Xinlei Zou1Wujiang Shi2Jianjun Gao3Chengru Yang4Yifei Ge5Zhaoqiang Xu6Shaowu Bi7Xiangyu Zhong8General Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, ChinaGeneral Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, ChinaGeneral Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, ChinaGeneral Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, ChinaGeneral Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, ChinaGeneral Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, ChinaGeneral Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, ChinaGeneral Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, ChinaGeneral Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China; For correspondence: Xiangyu ZhongMetabolic dysfunction–associated steatohepatitis (MASH) is a severe form of metabolic dysfunction–associated fatty liver disease metabolic dysfunction-associated steatohepatitis , characterized by hepatic steatosis, inflammation, and fibrosis. This study investigates the role and potential mechanisms of metallothionein 1B (MT1B) in MASH through bioinformatics analysis and experimental validation. quantitative reverse transcription PCR and Western blot analyses confirm that MT1B expression is significantly downregulated in liver tissues of MASH patients, in high-fat diet–induced mouse models, and in hepatocytes induced by FFAs. Further functional experiments show that upregulation of MT1B reduces intracellular triglycerides and total cholesterol levels, lipid droplet formation, and proinflammatory factors. In vivo experiments demonstrate that specific downregulation of hepatic MT1B expression via AAV8-shMT1B injection significantly increases triglyceride and total cholesterol levels, exacerbates lipid accumulation, and markedly elevates liver fibrosis and inflammatory factor expression. RNA-seq and bioinformatics analyses show that the AKT/PI3K pathway is significantly suppressed in MT1B-overexpressing cells. Further experiments indicate that AKT inhibition can reverse the lipid metabolism disorders and inflammatory responses caused by MT1B downregulation. Additionally, Zinc can promote the nuclear translocation of MTF1, leading to its binding to the MT1B promoter, thereby upregulating MT1B expression and ultimately mitigating MASH progression. These findings suggest that zinc-regulated MT1B plays a critical role in lipid metabolism and inflammatory responses by regulating the AKT/PI3K signaling pathway, influencing MASH progression.http://www.sciencedirect.com/science/article/pii/S0022227524002062metabolic dysfunctionassociated steatohepatitisMT1BAKT/PI3KMTF1zinc |
| spellingShingle | Canghai Guan Xinlei Zou Wujiang Shi Jianjun Gao Chengru Yang Yifei Ge Zhaoqiang Xu Shaowu Bi Xiangyu Zhong Metallothionein 1B attenuates inflammation and hepatic steatosis in MASH by inhibiting the AKT/PI3K pathway Journal of Lipid Research metabolic dysfunction associated steatohepatitis MT1B AKT/PI3K MTF1 zinc |
| title | Metallothionein 1B attenuates inflammation and hepatic steatosis in MASH by inhibiting the AKT/PI3K pathway |
| title_full | Metallothionein 1B attenuates inflammation and hepatic steatosis in MASH by inhibiting the AKT/PI3K pathway |
| title_fullStr | Metallothionein 1B attenuates inflammation and hepatic steatosis in MASH by inhibiting the AKT/PI3K pathway |
| title_full_unstemmed | Metallothionein 1B attenuates inflammation and hepatic steatosis in MASH by inhibiting the AKT/PI3K pathway |
| title_short | Metallothionein 1B attenuates inflammation and hepatic steatosis in MASH by inhibiting the AKT/PI3K pathway |
| title_sort | metallothionein 1b attenuates inflammation and hepatic steatosis in mash by inhibiting the akt pi3k pathway |
| topic | metabolic dysfunction associated steatohepatitis MT1B AKT/PI3K MTF1 zinc |
| url | http://www.sciencedirect.com/science/article/pii/S0022227524002062 |
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