| First Author | Montefusco D | Year | 2024 |
| Journal | Cell Rep | Volume | 43 |
| Issue | 12 | Pages | 115054 |
| PubMed ID | 39661520 | Mgi Jnum | J:361357 |
| Mgi Id | MGI:7852038 | Doi | 10.1016/j.celrep.2024.115054 |
| Citation | Montefusco D, et al. (2024) SPTLC3 regulates plasma membrane sphingolipid composition to facilitate hepatic gluconeogenesis. Cell Rep 43(12):115054 |
| abstractText | SPTLC3, an inducible subunit of the serine palmitoyltransferase (SPT) complex, causes production of alternative sphingoid bases, including a 16-carbon dihydrosphingosine, whose biological function is only beginning to emerge. High-fat feeding induced SPTLC3 in the liver, prompting us to produce a liver-specific knockout mouse line. Following high-fat feeding, knockout mice showed decreased fasting blood glucose, and knockout primary hepatocytes showed suppressed glucose production, a core function of hepatocytes. Stable isotope tracing revealed suppression of the gluconeogenic pathway, finding that SPTLC3 was required to maintain expression of key gluconeogenic genes via adenylate cyclase/cyclic AMP (cAMP)/cAMP response element binding protein (CREB) signaling. Additionally, by employing a combination of a recently developed lipidomics methodology, exogenous C14/C16 fatty acid treatment, and in situ adenylate cyclase activity, we implicated a functional interaction between sphingomyelin with a d16 backbone and adenylate cyclase at the plasma membrane. This work pinpoints a specific sphingolipid-protein functional interaction with broad implications for understanding sphingolipid signaling and metabolic disease. |
