{"title":"鞘磷脂合成酶相关蛋白是丝氨酸棕榈酰转移酶的调节因子。","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":"{\"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. 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引用次数: 0
摘要
鞘磷脂合成酶相关蛋白(Sphingomyelin synthase related protein, SMSr)属于SMS家族,但不能合成SM。我们报道SMSr是一种磷脂酰乙醇胺特异性磷脂酶C,与代谢功能障碍相关的脂肪肝(MAFLD)相关。然而,其机制尚不清楚。基于人类基因型组织表达项目样本的分层聚类,我们发现SMSr和鞘脂生物合成关键酶丝氨酸棕榈酰转移酶(SPT)以及某些鞘脂代谢相关基因在肝脏和脂肪组织中属于同一共表达簇。我们还发现Smsr的表达与Sptlc1和Sptlc2在两性组织中的表达呈正相关。在小鼠研究中,我们发现Smsr过表达诱导而Smsr敲除(KO)(在高脂肪饮食下)降低SPT活性,从而影响大多数测试的鞘脂。此外,我们发现PE治疗逆转Smsr过表达介导的SPTLC2上调。PE补充剂也以剂量依赖的方式降低肝微粒体SPT活性。此外,我们证明了SMSr在体内与SPTLC2相互作用。因此,SMSr作为鞘脂生物合成途径的成员,调控SPT。SPT活性的扰动与MAFLD和心血管疾病的预防有关。然而,迄今为止,寻找spt特异性抑制剂作为药物的方法尚未成功。重要的是,全球Smsr KO小鼠是健康的;因此,通过降低PE,通过SMSr/PE- plc活性介导抑制SPT活性,可能为预防和治疗mald提供新的途径。
Sphingomyelin Synthase Related Protein Is a Regulator of Serine Palmitoyltransferase.
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.