{"title":"Sphingomyelin Synthase Related Protein Is a Regulator of Serine Palmitoyltransferase.","authors":"Xiang Li, Zhiqiang Li, Yeun-Po Chiang, Tilla Worgall, Tade Souaiaia, Xian-Cheng Jiang","doi":"10.1016/j.jlr.2025.100908","DOIUrl":null,"url":null,"abstract":"<p><p>Sphingomyelin synthase related protein (SMSr) belongs to SMS family, however, it cannot synthesize SM. We reported that SMSr is a phosphatidylethanolamine-specific phospholipase C which is associated with metabolic dysfunction-associated fatty liver disease (MAFLD). However, the mechanism is unknown. Based on hierarchical clustering of the samples from human Genotype-Tissue Expression project, we found that SMSr and serine palmitoyltransferase (SPT), the key enzyme for sphingolipid biosynthesis, as well as certain sphingolipid metabolism related genes belong to the same co-expression cluster in the liver and adipose tissues. We also found that Smsr expression is positively associated with Sptlc1 and Sptlc2 expression in both tissues of both genders. In mouse study, we found that Smsr overexpression induced while Smsr knockout (KO) (under a high fat diet) reduced SPT activity, thus, influencing most of tested sphingolipids. Further, we found that PE treatment reversed Smsr overexpression-mediated SPTLC2 upregulation. PE supplement also reduced liver microsome SPT activity in a dose-dependent manner. Furthermore, we demonstrated that SMSr interacts with SPTLC2 in vivo. Thus, SMSr, as a member in sphingolipid biosynthesis pathway, regulates SPT. Perturbation of SPT activity has been linked to the prevention of MAFLD and cardiovascular diseases. However, the approach to finding a SPT-specific inhibitor, as a drug, has not been successful so far. Importantly, global Smsr KO mice are viable and healthy; therefore, inhibiting SPT activity by reducing PE, mediated by SMSr/PE-PLC activity, could provide a novel approach for preventing and treating MAFLD.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100908"},"PeriodicalIF":4.1000,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Lipid Research","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.jlr.2025.100908","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Sphingomyelin synthase related protein (SMSr) belongs to SMS family, however, it cannot synthesize SM. We reported that SMSr is a phosphatidylethanolamine-specific phospholipase C which is associated with metabolic dysfunction-associated fatty liver disease (MAFLD). However, the mechanism is unknown. Based on hierarchical clustering of the samples from human Genotype-Tissue Expression project, we found that SMSr and serine palmitoyltransferase (SPT), the key enzyme for sphingolipid biosynthesis, as well as certain sphingolipid metabolism related genes belong to the same co-expression cluster in the liver and adipose tissues. We also found that Smsr expression is positively associated with Sptlc1 and Sptlc2 expression in both tissues of both genders. In mouse study, we found that Smsr overexpression induced while Smsr knockout (KO) (under a high fat diet) reduced SPT activity, thus, influencing most of tested sphingolipids. Further, we found that PE treatment reversed Smsr overexpression-mediated SPTLC2 upregulation. PE supplement also reduced liver microsome SPT activity in a dose-dependent manner. Furthermore, we demonstrated that SMSr interacts with SPTLC2 in vivo. Thus, SMSr, as a member in sphingolipid biosynthesis pathway, regulates SPT. Perturbation of SPT activity has been linked to the prevention of MAFLD and cardiovascular diseases. However, the approach to finding a SPT-specific inhibitor, as a drug, has not been successful so far. Importantly, global Smsr KO mice are viable and healthy; therefore, inhibiting SPT activity by reducing PE, mediated by SMSr/PE-PLC activity, could provide a novel approach for preventing and treating MAFLD.
期刊介绍:
The Journal of Lipid Research (JLR) publishes original articles and reviews in the broadly defined area of biological lipids. We encourage the submission of manuscripts relating to lipids, including those addressing problems in biochemistry, molecular biology, structural biology, cell biology, genetics, molecular medicine, clinical medicine and metabolism. Major criteria for acceptance of articles are new insights into mechanisms of lipid function and metabolism and/or genes regulating lipid metabolism along with sound primary experimental data. Interpretation of the data is the authors’ responsibility, and speculation should be labeled as such. Manuscripts that provide new ways of purifying, identifying and quantifying lipids are invited for the Methods section of the Journal. JLR encourages contributions from investigators in all countries, but articles must be submitted in clear and concise English.