Altered mitochondrial unfolded protein response and FGF21 secretion in MASLD progression and the effect of exercise intervention
Abstract A high-calorie diet and lack of exercise are the most important risk factors contributing to metabolic dysfunction-associated steatotic liver disease (MASLD) initiation and progression. The precise molecular mechanisms of mitochondrial function alteration during MASLD development remain to...
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Nature Portfolio
2025-01-01
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| Online Access: | https://doi.org/10.1038/s41598-025-87190-6 |
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| author | Xinmeng Yuan Wen Sun Ye Xu Mengqi Xiang Yaran Gao Wanyu Feng Hongjian Xiao Liumei Zhang Qiang Tang Jiao Lu Yuan Zhang |
| author_facet | Xinmeng Yuan Wen Sun Ye Xu Mengqi Xiang Yaran Gao Wanyu Feng Hongjian Xiao Liumei Zhang Qiang Tang Jiao Lu Yuan Zhang |
| author_sort | Xinmeng Yuan |
| collection | DOAJ |
| description | Abstract A high-calorie diet and lack of exercise are the most important risk factors contributing to metabolic dysfunction-associated steatotic liver disease (MASLD) initiation and progression. The precise molecular mechanisms of mitochondrial function alteration during MASLD development remain to be fully elucidated. In this study, a total of 60 male C57BL/6J mice were maintained on a normal or amylin liver NASH (AMLN) diet for 6 or 10 weeks. Some of the mice were then subjected to voluntary wheel running, while the other mice were fed a normal or AMLN diet until 14 and 18 weeks. The results showed that hepatic lipid deposition and the PERK-eIF2α-ATF4 pathway were significantly increased with prolonged duration of AMLN diet. However, expression of mitochondrial unfolded protein response (UPRmt) genes and mitokine FGF21 secretion were significantly enhanced in the 14-week AMLN diet mice, but were markedly reduced with the excessive lipid deposition induced by longer AMLN diet. Additionally, the exercise intervention acts as a regulator to optimize UPRmt signal transduction and to enhance mitochondrial homeostasis by improving mitochondrial function, reversing the UPRmt activation pattern, and increasing FGF21 secretion, which plays a pivotal role in delaying the occurrence and development of MASLD. |
| format | Article |
| id | doaj-art-b0c1263aff2143caa764c72dd12d2ccd |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-b0c1263aff2143caa764c72dd12d2ccd2025-02-02T12:20:34ZengNature PortfolioScientific Reports2045-23222025-01-0115111410.1038/s41598-025-87190-6Altered mitochondrial unfolded protein response and FGF21 secretion in MASLD progression and the effect of exercise interventionXinmeng Yuan0Wen Sun1Ye Xu2Mengqi Xiang3Yaran Gao4Wanyu Feng5Hongjian Xiao6Liumei Zhang7Qiang Tang8Jiao Lu9Yuan Zhang10School of Sports and Health, Nanjing Sport InstituteSchool of Sports and Health, Nanjing Sport InstituteSchool of Sports and Health, Nanjing Sport InstituteSchool of Sports and Health, Nanjing Sport InstituteSchool of Sports and Health, Nanjing Sport InstituteJiangsu Collaborative Innovation Center for Sport and Health ProjectSchool of Sports and Health, Nanjing Sport InstituteSchool of Sports and Health, Nanjing Sport InstituteSchool of Sports and Health, Nanjing Sport InstituteSchool of Sports and Health, Nanjing Sport InstituteSchool of Sports and Health, Nanjing Sport InstituteAbstract A high-calorie diet and lack of exercise are the most important risk factors contributing to metabolic dysfunction-associated steatotic liver disease (MASLD) initiation and progression. The precise molecular mechanisms of mitochondrial function alteration during MASLD development remain to be fully elucidated. In this study, a total of 60 male C57BL/6J mice were maintained on a normal or amylin liver NASH (AMLN) diet for 6 or 10 weeks. Some of the mice were then subjected to voluntary wheel running, while the other mice were fed a normal or AMLN diet until 14 and 18 weeks. The results showed that hepatic lipid deposition and the PERK-eIF2α-ATF4 pathway were significantly increased with prolonged duration of AMLN diet. However, expression of mitochondrial unfolded protein response (UPRmt) genes and mitokine FGF21 secretion were significantly enhanced in the 14-week AMLN diet mice, but were markedly reduced with the excessive lipid deposition induced by longer AMLN diet. Additionally, the exercise intervention acts as a regulator to optimize UPRmt signal transduction and to enhance mitochondrial homeostasis by improving mitochondrial function, reversing the UPRmt activation pattern, and increasing FGF21 secretion, which plays a pivotal role in delaying the occurrence and development of MASLD.https://doi.org/10.1038/s41598-025-87190-6Mitochondrial unfolded protein responseHepatic lipid accumulationExercise interventionAMLN dietMASLD progression |
| spellingShingle | Xinmeng Yuan Wen Sun Ye Xu Mengqi Xiang Yaran Gao Wanyu Feng Hongjian Xiao Liumei Zhang Qiang Tang Jiao Lu Yuan Zhang Altered mitochondrial unfolded protein response and FGF21 secretion in MASLD progression and the effect of exercise intervention Scientific Reports Mitochondrial unfolded protein response Hepatic lipid accumulation Exercise intervention AMLN diet MASLD progression |
| title | Altered mitochondrial unfolded protein response and FGF21 secretion in MASLD progression and the effect of exercise intervention |
| title_full | Altered mitochondrial unfolded protein response and FGF21 secretion in MASLD progression and the effect of exercise intervention |
| title_fullStr | Altered mitochondrial unfolded protein response and FGF21 secretion in MASLD progression and the effect of exercise intervention |
| title_full_unstemmed | Altered mitochondrial unfolded protein response and FGF21 secretion in MASLD progression and the effect of exercise intervention |
| title_short | Altered mitochondrial unfolded protein response and FGF21 secretion in MASLD progression and the effect of exercise intervention |
| title_sort | altered mitochondrial unfolded protein response and fgf21 secretion in masld progression and the effect of exercise intervention |
| topic | Mitochondrial unfolded protein response Hepatic lipid accumulation Exercise intervention AMLN diet MASLD progression |
| url | https://doi.org/10.1038/s41598-025-87190-6 |
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