Sphingomyelin synthase-related protein is a regulator of serine palmitoyltransferase.

Sphingomyelin synthase-related protein (SMSr) belongs to the 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 the 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 a mouse study, we found that Smsr overexpression induced while Smsr knockout (KO) (under a high-fat diet) reduced SPT activity, thus, influencing most of the 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 the 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 an 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.