Smpd3, or sphingomyelin phosphodiesterase 3, is a lipid-metabolizing enzyme. It is crucial for sphingomyelin hydrolysis, producing ceramide, and is involved in pathways such as the intestinal FXR-SMPD3 pathway. It has importance in various biological processes including membrane sphingolipid metabolism, neural crest EMT, and postnatal liver development [1,4,5]. Genetic models, like knockout mouse models, have been valuable in studying its functions.

In a mouse model where Smpd3 was ablated in Osx-expressing chondrocytes and osteoblasts during early skeletogenesis, there were delayed extracellular matrix mineralization and severe skeletal deformities. Postnatal ablation in 3-month-old mice led to a mild bone mineralization defect and increased unmineralized osteoid in fractured tibiae [6]. In the context of colitis, sedanolide alleviated DSS-induced colitis in mice by inhibiting the FXR-SMPD3 pathway to stimulate ceramide synthesis [1]. In NAFLD progression, nicotine activates intestinal AMPKα which promotes SMPD3 phosphorylation, increasing intestinal ceramide formation and contributing to NAFLD progression to NASH [2]. Hepatic SMPD3 disruption alleviates steatohepatitis as it disrupts membrane sphingomyelin-ceramide balance [3]. Also, in neuronal cells, Smpd3 deficiency in the Golgi compartment of neurons in smpd3-/-mouse brain leads to progressive cognitive impairment [7].

In summary, Smpd3 is essential for processes like membrane lipid metabolism, bone development, and is implicated in diseases such as colitis, NAFLD, steatohepatitis, and neurodegenerative diseases. Gene knockout mouse models have been instrumental in revealing its role in these biological processes and disease conditions, providing insights into potential therapeutic targets for related diseases.