SPTLC3 regulates plasma membrane sphingolipid composition to facilitate hepatic gluconeogenesis
Summary: 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 pro...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-12-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724014050 |
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| Summary: | Summary: 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. |
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| ISSN: | 2211-1247 |