Ethyl Lactate Ameliorates Hepatic Steatosis and Acute‐on‐Chronic Liver Injury in Alcohol‐Associated Liver Disease by Inducing Fibroblast Growth Factor 21
Abstract Aberrant upregulation of hepatic lipogenesis induced by chronic and excessive alcohol consumption is a critical driver of the progression of alcohol‐associated liver disease (ALD), however, no effective approaches inhibiting lipogenesis are currently available for treating ALD patients. Mor...
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202409516 |
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| author | Yang Jiang Shuang Wei Shiming Shen Yuxiao Liu Weitong Su Dong Ding Zengpeng Zheng Haokai Yu Tingting Zhang Qiuli Yang Jiuxiang Zhao Yi Shen Xia Fang Liangcai Lin Dongguang Xiao Aoyuan Cui Qin Wan Yadong Zhang Yu Li Cuiying Zhang |
| author_facet | Yang Jiang Shuang Wei Shiming Shen Yuxiao Liu Weitong Su Dong Ding Zengpeng Zheng Haokai Yu Tingting Zhang Qiuli Yang Jiuxiang Zhao Yi Shen Xia Fang Liangcai Lin Dongguang Xiao Aoyuan Cui Qin Wan Yadong Zhang Yu Li Cuiying Zhang |
| author_sort | Yang Jiang |
| collection | DOAJ |
| description | Abstract Aberrant upregulation of hepatic lipogenesis induced by chronic and excessive alcohol consumption is a critical driver of the progression of alcohol‐associated liver disease (ALD), however, no effective approaches inhibiting lipogenesis are currently available for treating ALD patients. Moreover, little is known about whether and how nonethanol ingredients in alcoholic beverages regulate the pathogenesis of ALD. Here the discovery of a small molecule that activates the production and secretion of fibroblast growth factor 21 (FGF21) is reported. It is shown that the activator ethyl lactate, a nonethanol ingredient found in distilled liquors, ameliorates alcoholic hepatosteatosis, inflammation and acute‐on‐chronic liver injury by stimulating FGF21. In response to chronic‐plus‐binge ethanol feeding or fasting, ethyl lactate mimics lipogenesis lowering effects by stimulating FGF21 production through the NAD+‐dependent deacetylase sirtuin 1 (SIRT1) signaling pathway. These ethyl lactate‐mediated beneficial effects are abolished by inhibition of SIRT1 through injection of EX527. Importantly, FGF21 deficiency in hepatocytes blocks the downregulation of lipogenesis by ethyl lactate and exacerbates alcoholic steatosis, inflammation and liver injury. The regulatory mechanism is discussed during the pathophysiological conditions and suggests new lines of research into the therapeutic use of a foodborne small molecule ethyl lactate. |
| format | Article |
| id | doaj-art-56771736fc2e4e1cb2b8635e8e5ef40b |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-56771736fc2e4e1cb2b8635e8e5ef40b2025-02-04T13:14:55ZengWileyAdvanced Science2198-38442025-02-01125n/an/a10.1002/advs.202409516Ethyl Lactate Ameliorates Hepatic Steatosis and Acute‐on‐Chronic Liver Injury in Alcohol‐Associated Liver Disease by Inducing Fibroblast Growth Factor 21Yang Jiang0Shuang Wei1Shiming Shen2Yuxiao Liu3Weitong Su4Dong Ding5Zengpeng Zheng6Haokai Yu7Tingting Zhang8Qiuli Yang9Jiuxiang Zhao10Yi Shen11Xia Fang12Liangcai Lin13Dongguang Xiao14Aoyuan Cui15Qin Wan16Yadong Zhang17Yu Li18Cuiying Zhang19State Key Laboratory of Food Nutrition and Safety College of Biotechnology Tianjin University of Science and Technology Tianjin 300457 ChinaCAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 ChinaState Key Laboratory of Food Nutrition and Safety College of Biotechnology Tianjin University of Science and Technology Tianjin 300457 ChinaCAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 ChinaCAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 ChinaCAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 ChinaCAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 ChinaState Key Laboratory of Food Nutrition and Safety College of Biotechnology Tianjin University of Science and Technology Tianjin 300457 ChinaCAS Engineering Laboratory for Nutrition Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 ChinaCAS Engineering Laboratory for Nutrition Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 ChinaCAS Engineering Laboratory for Nutrition Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 ChinaSichuan Langjiu Co. Ltd Gulin Sichuan 646523 ChinaState Key Laboratory of Food Nutrition and Safety College of Biotechnology Tianjin University of Science and Technology Tianjin 300457 ChinaState Key Laboratory of Food Nutrition and Safety College of Biotechnology Tianjin University of Science and Technology Tianjin 300457 ChinaState Key Laboratory of Food Nutrition and Safety College of Biotechnology Tianjin University of Science and Technology Tianjin 300457 ChinaCAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 ChinaDepartment of Endocrinology and Metabolism Metabolic Vascular Disease Key Laboratory of Sichuan Province The Affiliated Hospital of Southwest Medical University Luzhou Sichuan 646000 ChinaSichuan Langjiu Co. Ltd Gulin Sichuan 646523 ChinaCAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200031 ChinaState Key Laboratory of Food Nutrition and Safety College of Biotechnology Tianjin University of Science and Technology Tianjin 300457 ChinaAbstract Aberrant upregulation of hepatic lipogenesis induced by chronic and excessive alcohol consumption is a critical driver of the progression of alcohol‐associated liver disease (ALD), however, no effective approaches inhibiting lipogenesis are currently available for treating ALD patients. Moreover, little is known about whether and how nonethanol ingredients in alcoholic beverages regulate the pathogenesis of ALD. Here the discovery of a small molecule that activates the production and secretion of fibroblast growth factor 21 (FGF21) is reported. It is shown that the activator ethyl lactate, a nonethanol ingredient found in distilled liquors, ameliorates alcoholic hepatosteatosis, inflammation and acute‐on‐chronic liver injury by stimulating FGF21. In response to chronic‐plus‐binge ethanol feeding or fasting, ethyl lactate mimics lipogenesis lowering effects by stimulating FGF21 production through the NAD+‐dependent deacetylase sirtuin 1 (SIRT1) signaling pathway. These ethyl lactate‐mediated beneficial effects are abolished by inhibition of SIRT1 through injection of EX527. Importantly, FGF21 deficiency in hepatocytes blocks the downregulation of lipogenesis by ethyl lactate and exacerbates alcoholic steatosis, inflammation and liver injury. The regulatory mechanism is discussed during the pathophysiological conditions and suggests new lines of research into the therapeutic use of a foodborne small molecule ethyl lactate.https://doi.org/10.1002/advs.202409516alcohol‐associated liver diseaseethyl lactatefibroblast growth factor 21hepatic steatosislipogenesis |
| spellingShingle | Yang Jiang Shuang Wei Shiming Shen Yuxiao Liu Weitong Su Dong Ding Zengpeng Zheng Haokai Yu Tingting Zhang Qiuli Yang Jiuxiang Zhao Yi Shen Xia Fang Liangcai Lin Dongguang Xiao Aoyuan Cui Qin Wan Yadong Zhang Yu Li Cuiying Zhang Ethyl Lactate Ameliorates Hepatic Steatosis and Acute‐on‐Chronic Liver Injury in Alcohol‐Associated Liver Disease by Inducing Fibroblast Growth Factor 21 Advanced Science alcohol‐associated liver disease ethyl lactate fibroblast growth factor 21 hepatic steatosis lipogenesis |
| title | Ethyl Lactate Ameliorates Hepatic Steatosis and Acute‐on‐Chronic Liver Injury in Alcohol‐Associated Liver Disease by Inducing Fibroblast Growth Factor 21 |
| title_full | Ethyl Lactate Ameliorates Hepatic Steatosis and Acute‐on‐Chronic Liver Injury in Alcohol‐Associated Liver Disease by Inducing Fibroblast Growth Factor 21 |
| title_fullStr | Ethyl Lactate Ameliorates Hepatic Steatosis and Acute‐on‐Chronic Liver Injury in Alcohol‐Associated Liver Disease by Inducing Fibroblast Growth Factor 21 |
| title_full_unstemmed | Ethyl Lactate Ameliorates Hepatic Steatosis and Acute‐on‐Chronic Liver Injury in Alcohol‐Associated Liver Disease by Inducing Fibroblast Growth Factor 21 |
| title_short | Ethyl Lactate Ameliorates Hepatic Steatosis and Acute‐on‐Chronic Liver Injury in Alcohol‐Associated Liver Disease by Inducing Fibroblast Growth Factor 21 |
| title_sort | ethyl lactate ameliorates hepatic steatosis and acute on chronic liver injury in alcohol associated liver disease by inducing fibroblast growth factor 21 |
| topic | alcohol‐associated liver disease ethyl lactate fibroblast growth factor 21 hepatic steatosis lipogenesis |
| url | https://doi.org/10.1002/advs.202409516 |
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