Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis
Nonalcoholic steatohepatitis (NASH), is the advanced stage of nonalcoholic fatty liver disease (NAFLD) with rapidly rising global prevalence. It is featured with severe hepatocyte apoptosis, inflammation and hepatic lipogenesis. The drugs directly targeting the processes of steatosis, inflammation a...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | Metabolism Open |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589936823000397 |
| _version_ | 1797249072333062144 |
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| author | Yibing Wang Hanhan Yu Zhipeng Cen Yutong Zhu Wenyi Wu |
| author_facet | Yibing Wang Hanhan Yu Zhipeng Cen Yutong Zhu Wenyi Wu |
| author_sort | Yibing Wang |
| collection | DOAJ |
| description | Nonalcoholic steatohepatitis (NASH), is the advanced stage of nonalcoholic fatty liver disease (NAFLD) with rapidly rising global prevalence. It is featured with severe hepatocyte apoptosis, inflammation and hepatic lipogenesis. The drugs directly targeting the processes of steatosis, inflammation and fibrosis are currently under clinical investigation. Nevertheless, the long-term ineffectiveness and remarkable adverse effects are well documented, and new concepts are required to tackle with the root causes of NASH progression. We critically assess the recently validated drug targets that regulate the systemic metabolism to ameliorate NASH. Thermogenesis promoted by mitochondrial uncouplers restores systemic energy expenditure. Furthermore, regulation of mitochondrial proteases and proteins that are pivotal for intracellular metabolic homeostasis normalize mitochondrial function. Secreted proteins also improve systemic metabolism, and NASH is ameliorated by agonizing receptors of secreted proteins with small molecules. We analyze the drug design, the advantages and shortcomings of these novel drug candidates. Meanwhile, the structural modification of current NASH therapeutics significantly increased their selectivity, efficacy and safety. Furthermore, the arising CRISPR-Cas9 screen strategy on liver organoids has enabled the identification of new genes that mediate lipid metabolism, which may serve as promising drug targets. In summary, this article discusses the in-depth novel mechanisms and the multidisciplinary approaches, and they provide new horizons to treat NASH. |
| first_indexed | 2024-03-08T21:49:56Z |
| format | Article |
| id | doaj.art-489ced9c9ff54f7099d091529cee1255 |
| institution | Directory Open Access Journal |
| issn | 2589-9368 |
| language | English |
| last_indexed | 2024-04-24T20:24:40Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Metabolism Open |
| spelling | doaj.art-489ced9c9ff54f7099d091529cee12552024-03-22T05:40:29ZengElsevierMetabolism Open2589-93682024-03-0121100267Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitisYibing Wang0Hanhan Yu1Zhipeng Cen2Yutong Zhu3Wenyi Wu4School of Kinesiology, Shanghai University of Sport, Shanghai, 200438, China; Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, China; Corresponding author. School of Kinesiology, Shanghai University of Sport, Shanghai, 200438, China.School of Kinesiology, Shanghai University of Sport, Shanghai, 200438, ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, ChinaSchool of Kinesiology, Shanghai University of Sport, Shanghai, 200438, ChinaSchool of Kinesiology, Shanghai University of Sport, Shanghai, 200438, ChinaNonalcoholic steatohepatitis (NASH), is the advanced stage of nonalcoholic fatty liver disease (NAFLD) with rapidly rising global prevalence. It is featured with severe hepatocyte apoptosis, inflammation and hepatic lipogenesis. The drugs directly targeting the processes of steatosis, inflammation and fibrosis are currently under clinical investigation. Nevertheless, the long-term ineffectiveness and remarkable adverse effects are well documented, and new concepts are required to tackle with the root causes of NASH progression. We critically assess the recently validated drug targets that regulate the systemic metabolism to ameliorate NASH. Thermogenesis promoted by mitochondrial uncouplers restores systemic energy expenditure. Furthermore, regulation of mitochondrial proteases and proteins that are pivotal for intracellular metabolic homeostasis normalize mitochondrial function. Secreted proteins also improve systemic metabolism, and NASH is ameliorated by agonizing receptors of secreted proteins with small molecules. We analyze the drug design, the advantages and shortcomings of these novel drug candidates. Meanwhile, the structural modification of current NASH therapeutics significantly increased their selectivity, efficacy and safety. Furthermore, the arising CRISPR-Cas9 screen strategy on liver organoids has enabled the identification of new genes that mediate lipid metabolism, which may serve as promising drug targets. In summary, this article discusses the in-depth novel mechanisms and the multidisciplinary approaches, and they provide new horizons to treat NASH.http://www.sciencedirect.com/science/article/pii/S2589936823000397NASHDrug targetsMechanismsEnergy expenditureMetabolic homeostasisDrug discovery |
| spellingShingle | Yibing Wang Hanhan Yu Zhipeng Cen Yutong Zhu Wenyi Wu Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis Metabolism Open NASH Drug targets Mechanisms Energy expenditure Metabolic homeostasis Drug discovery |
| title | Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis |
| title_full | Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis |
| title_fullStr | Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis |
| title_full_unstemmed | Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis |
| title_short | Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis |
| title_sort | drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis |
| topic | NASH Drug targets Mechanisms Energy expenditure Metabolic homeostasis Drug discovery |
| url | http://www.sciencedirect.com/science/article/pii/S2589936823000397 |
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