Ceramide and diacylglycerol (DAG) are bioactive lipids and mediate many cellular signaling pathways. Sphingomyelin synthase (SMS) is the single metabolic link between the two, while SMS2 is the only SMS form located at the plasma membrane. SMS2 functions were investigated in HepG2 cell lines stably expressing SMS2. SMS2 overexpression did not alter sphingomyelin (SM), phosphatidylcholine (PC), or ceramide levels. DAG content increased by approx. 40% and led to downregulation of DAG-dependent protein kinase C (PKC). SMS2 overexpression also induced senescence, characterized by positivity for β-galactosidase activity and heterochromatin foci. HepG2-SMS2 cells exhibited protruded mitochondria and suppressed mitochondrial respiration rates. ATP production and the abundance of Complex V were substantially lower in HepG2-SMS2 cells as compared to controls. SMS2 overexpression was associated with inflammasome activation based on increases in IL-1β and nlpr3 mRNA levels. HepG2-SMS2 cells exhibited lipid droplet accumulation, constitutive activation of AMPK based on elevated ¹⁷²Thr phosphorylation, increased AMPK abundance, and insensitivity to insulin suppression of AMPK. Thus, our results show that SMS2 regulates DAG homeostasis and signaling in hepatocytes and also provide proof of principle for the concept that offset in bioactive lipids’ production at the plasma membrane can drive the senescence program in association with steatosis and, seemingly, by cell-autonomous mechanisms.

Bone homeostasis is a dynamic process governed by the balanced activity of osteoblasts and osteoclasts, tightly regulated through complex signaling networks. Emerging evidence highlights sphingolipid metabolism as a critical modulator of skeletal integrity, influencing bone remodeling in both health and disease. Each individual step, however, appears to have a unique role in these processes, with some overlap in function that is not well understood yet. This review explores the interplay between sphingolipid metabolism and bone homeostasis. It provides a comprehensive overview of the diverse roles of the various sphingolipid metabolic enzymes in bone remodeling and the maintenance of bone health. Special focus is given to the key enzymes from the de novo and turnover pathways that have been shown to play a pivotal role in modulating osteoblast and osteoclast differentiation, survival, and function, thereby impacting bone formation and resorption. Emerging data also suggest that alterations in sphingolipid metabolism may serve as biomarkers or therapeutic targets in metabolic bone diseases. Understanding these sphingolipid-mediated mechanisms opens new avenues for targeted interventions in bone disorders. It also highlights the need for further research into the therapeutic potential of modulating the sphingolipid metabolic pathway.