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Hepatic sphingomyelin phosphodiesterase 3 promotes steatohepatitis by disrupting membrane sphingolipid metabolism

文献类型：期刊论文

作者Jiang, Jie8,9; Gao, Yuqing7,9; Wang, Jiang6,9; Huang, Yan5; Yang, Rong4; Zhang, Yongxin7,9; Ma, Yuandi7,9; Wen, Yingquan9; Luo, Gongkai7,9; Zhang, Shurui3,6
刊名CELL METABOLISM
出版日期2025-05-06
卷号37期号:5页码:32
ISSN号1550-4131
DOI10.1016/j.cmet.2025.01.016
英文摘要Metabolic-dysfunction-associated steatohepatitis (MASH) remains a major health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption or pharmacological inhibition of SMPD3 alleviates MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. Although healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses sirtuin 1 (SIRT1), triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes disease progression by enhancing caveolae-dependent lipid uptake and extracellular vesicle secretion from steatotic hepatocytes to exacerbate inflammation and fibrosis. Consequently, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid metabolism and holds great promise for developing novel MASH therapies.
WOS关键词NECROSIS-FACTOR-ALPHA ; NONALCOHOLIC STEATOHEPATITIS ; METHYLATION ANALYSIS ; LIVER ; DISEASE ; NASH ; THERAPEUTICS ; ACTIVATORS ; STEATOSIS ; PATHWAY
资助项目National Natural Science Foundation of China[92253305] ; National Natural Science Foundation of China[82130105] ; National Natural Science Foundation of China[22337003] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[82322063] ; National Natural Science Foundation of China[82104253] ; National Key Research and Development Program of China[2021YFA1301200] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB39020600] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB0830402] ; Shanghai Municipal Science and Technol-ogy Major Project ; National Cancer Institute Intramural Research Program ; [82222071]
WOS研究方向Cell Biology ; Endocrinology & Metabolism
语种英语
WOS记录号WOS:001490208500001
出版者CELL PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/318198]  
专题新药研究国家重点实验室
通讯作者Liu, Yameng; Liu, Hong; Xie, Qing; Xie, Cen
作者单位1.NCI, NIH, Ctr Canc Res, Bethesda, MD 20892 USA
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
4.Shanghai Jiao Tong Univ, Ctr Fatty Liver, Dept Gastroenterol, Xinhua Hosp,Sch Med, Shanghai 200092, Peoples R China
5.Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Infect Dis, Sch Med, Shanghai 200025, Peoples R China
6.Lingang Lab, Shanghai 200444, Peoples R China
7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
8.Shanghai Univ Tradit Chinese Med, Dept Lab Med, Longhua Hosp, Shanghai 200032, Peoples R China
9.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Jiang, Jie,Gao, Yuqing,Wang, Jiang,et al. Hepatic sphingomyelin phosphodiesterase 3 promotes steatohepatitis by disrupting membrane sphingolipid metabolism[J]. CELL METABOLISM,2025,37(5):32.
APA Jiang, Jie.,Gao, Yuqing.,Wang, Jiang.,Huang, Yan.,Yang, Rong.,...&Xie, Cen.(2025).Hepatic sphingomyelin phosphodiesterase 3 promotes steatohepatitis by disrupting membrane sphingolipid metabolism.CELL METABOLISM,37(5),32.
MLA Jiang, Jie,et al."Hepatic sphingomyelin phosphodiesterase 3 promotes steatohepatitis by disrupting membrane sphingolipid metabolism".CELL METABOLISM 37.5(2025):32.

入库方式： OAI收割

来源：上海药物研究所

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