Exercise inhibits JNK pathway activation and lipotoxicity via macrophage migration inhibitory factor in nonalcoholic fatty liver disease
The macrophage migration inhibitory factor (MIF) expressed in hepatocytes can limit steatosis during obesity. Lipotoxicity in nonalcoholic fatty liver disease is mediated in part by the activation of the stress kinase JNK, but whether MIF modulates JNK in lipotoxicity is unknown. In this study, we i...
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2022.961231/full |
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| author | Ni Cui Hui Li Yaoshan Dun Yaoshan Dun Yaoshan Dun Jeffrey W. Ripley-Gonzalez Baiyang You Baiyang You Dezhao Li Yuan Liu Ling Qiu Cui Li Suixin Liu Suixin Liu |
| author_facet | Ni Cui Hui Li Yaoshan Dun Yaoshan Dun Yaoshan Dun Jeffrey W. Ripley-Gonzalez Baiyang You Baiyang You Dezhao Li Yuan Liu Ling Qiu Cui Li Suixin Liu Suixin Liu |
| author_sort | Ni Cui |
| collection | DOAJ |
| description | The macrophage migration inhibitory factor (MIF) expressed in hepatocytes can limit steatosis during obesity. Lipotoxicity in nonalcoholic fatty liver disease is mediated in part by the activation of the stress kinase JNK, but whether MIF modulates JNK in lipotoxicity is unknown. In this study, we investigated the role of MIF in regulating JNK activation and high-fat fostered liver lipotoxicity during simultaneous exercise treatment. Fifteen mice were equally divided into three groups: normal diet, high-fat diet, and high-fat and exercise groups. High-fat feeding for extended periods elicited evident hyperlipemia, liver steatosis, and cell apoptosis in mice, with inhibited MIF and activated downstream MAPK kinase 4 phosphorylation and JNK. These effects were then reversed following prescribed swimming exercise, indicating that the advent of exercise could prevent liver lipotoxicity induced by lipid overload and might correlate to the action of modulating MIF and its downstream JNK pathway. Similar detrimental effects of lipotoxicity were observed in in vitro HepG2 cells palmitic acid treatment. Suppressed JNK reduced the hepatocyte lipotoxicity by regulating the BCL family, and the excess JNK activation could also be attenuated through MIF supplementation or exacerbated by MIF siRNA administration. The results found suggest that exercise reduces lipotoxicity and inhibits JNK activation by modulating endogenous hepatic MIF in NAFLD. These findings have clinical implications for the prevention and intervention of patients with immoderate diet evoked NAFLD. |
| first_indexed | 2024-04-11T20:05:33Z |
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| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-11T20:05:33Z |
| publishDate | 2022-09-01 |
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| series | Frontiers in Endocrinology |
| spelling | doaj.art-1a60273714f64030aad4dfd41dcc77532022-12-22T04:05:20ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-09-011310.3389/fendo.2022.961231961231Exercise inhibits JNK pathway activation and lipotoxicity via macrophage migration inhibitory factor in nonalcoholic fatty liver diseaseNi Cui0Hui Li1Yaoshan Dun2Yaoshan Dun3Yaoshan Dun4Jeffrey W. Ripley-Gonzalez5Baiyang You6Baiyang You7Dezhao Li8Yuan Liu9Ling Qiu10Cui Li11Suixin Liu12Suixin Liu13Division of Cardiac Rehabilitation, Department of Physical Medicine and Rehabilitation, Xiangya Hospital of Central South University, Changsha, ChinaDivision of Cardiac Rehabilitation, Department of Physical Medicine and Rehabilitation, Xiangya Hospital of Central South University, Changsha, ChinaDivision of Cardiac Rehabilitation, Department of Physical Medicine and Rehabilitation, Xiangya Hospital of Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, ChinaDivision of Preventive Cardiology, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United StatesDivision of Cardiac Rehabilitation, Department of Physical Medicine and Rehabilitation, Xiangya Hospital of Central South University, Changsha, ChinaDivision of Cardiac Rehabilitation, Department of Physical Medicine and Rehabilitation, Xiangya Hospital of Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, ChinaDivision of Cardiac Rehabilitation, Department of Physical Medicine and Rehabilitation, Xiangya Hospital of Central South University, Changsha, ChinaDivision of Cardiac Rehabilitation, Department of Physical Medicine and Rehabilitation, Xiangya Hospital of Central South University, Changsha, ChinaDivision of Cardiac Rehabilitation, Department of Physical Medicine and Rehabilitation, Xiangya Hospital of Central South University, Changsha, ChinaDivision of Cardiac Rehabilitation, Department of Physical Medicine and Rehabilitation, Xiangya Hospital of Central South University, Changsha, ChinaDivision of Cardiac Rehabilitation, Department of Physical Medicine and Rehabilitation, Xiangya Hospital of Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, ChinaThe macrophage migration inhibitory factor (MIF) expressed in hepatocytes can limit steatosis during obesity. Lipotoxicity in nonalcoholic fatty liver disease is mediated in part by the activation of the stress kinase JNK, but whether MIF modulates JNK in lipotoxicity is unknown. In this study, we investigated the role of MIF in regulating JNK activation and high-fat fostered liver lipotoxicity during simultaneous exercise treatment. Fifteen mice were equally divided into three groups: normal diet, high-fat diet, and high-fat and exercise groups. High-fat feeding for extended periods elicited evident hyperlipemia, liver steatosis, and cell apoptosis in mice, with inhibited MIF and activated downstream MAPK kinase 4 phosphorylation and JNK. These effects were then reversed following prescribed swimming exercise, indicating that the advent of exercise could prevent liver lipotoxicity induced by lipid overload and might correlate to the action of modulating MIF and its downstream JNK pathway. Similar detrimental effects of lipotoxicity were observed in in vitro HepG2 cells palmitic acid treatment. Suppressed JNK reduced the hepatocyte lipotoxicity by regulating the BCL family, and the excess JNK activation could also be attenuated through MIF supplementation or exacerbated by MIF siRNA administration. The results found suggest that exercise reduces lipotoxicity and inhibits JNK activation by modulating endogenous hepatic MIF in NAFLD. These findings have clinical implications for the prevention and intervention of patients with immoderate diet evoked NAFLD.https://www.frontiersin.org/articles/10.3389/fendo.2022.961231/fullexerciseNAFLD (non alcoholic fatty liver disease)MIF — macrophage migration inhibitory factorlipotocixityJNK |
| spellingShingle | Ni Cui Hui Li Yaoshan Dun Yaoshan Dun Yaoshan Dun Jeffrey W. Ripley-Gonzalez Baiyang You Baiyang You Dezhao Li Yuan Liu Ling Qiu Cui Li Suixin Liu Suixin Liu Exercise inhibits JNK pathway activation and lipotoxicity via macrophage migration inhibitory factor in nonalcoholic fatty liver disease Frontiers in Endocrinology exercise NAFLD (non alcoholic fatty liver disease) MIF — macrophage migration inhibitory factor lipotocixity JNK |
| title | Exercise inhibits JNK pathway activation and lipotoxicity via macrophage migration inhibitory factor in nonalcoholic fatty liver disease |
| title_full | Exercise inhibits JNK pathway activation and lipotoxicity via macrophage migration inhibitory factor in nonalcoholic fatty liver disease |
| title_fullStr | Exercise inhibits JNK pathway activation and lipotoxicity via macrophage migration inhibitory factor in nonalcoholic fatty liver disease |
| title_full_unstemmed | Exercise inhibits JNK pathway activation and lipotoxicity via macrophage migration inhibitory factor in nonalcoholic fatty liver disease |
| title_short | Exercise inhibits JNK pathway activation and lipotoxicity via macrophage migration inhibitory factor in nonalcoholic fatty liver disease |
| title_sort | exercise inhibits jnk pathway activation and lipotoxicity via macrophage migration inhibitory factor in nonalcoholic fatty liver disease |
| topic | exercise NAFLD (non alcoholic fatty liver disease) MIF — macrophage migration inhibitory factor lipotocixity JNK |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.961231/full |
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