Published on Fri Sep 17 2021

Hepatocyte serine palmitoyl transferase 2 deficiency promotes liver C16:0-ceramide accumulation through sphingomyelin hydrolysis and leads to liver damage and dysfunction in mice

Lallement, J., Raho, I., Merlen, G., Rainteau, D., Croyal, M., Schiffano, M., Kassis, N., Doignon, I., Soty, M., Krempf, M., Amouyal, C., Le Stunff, H., Magnan, C., Tordjmann, T., Cruciani-Guglielmacci, C.

Ceramides have been shown as lipotoxic inducers, which can trigger apoptosis, inflammation and disturb numerous cell signalling pathways leading to metabolic disorders such as type 2 diabetes (T2D) We aimed to determine the role of de novo hepatic ceramide synthesis on energy and liver homeostasis in mice.

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Abstract

Objectives: Ceramides have been shown as lipotoxic inducers, which can trigger apoptosis, inflammation and disturb numerous cell signalling pathways leading to metabolic disorders such as type 2 diabetes (T2D). In this study, we aimed to determine the role of de novo hepatic ceramide synthesis on energy and liver homeostasis in mice. Methods: In order to investigate hepatic role of de novo ceramides synthesis, we generated mice lacking serine palmitoyltransferase 2 (Sptlc2) in hepatocytes using the cre-lox system. SPTLC2 allows condensation of serine and palmitoylCoA and is the rate limiting-enzyme necessary for ceramide de novo synthesis. Sptlc2{Delta}Hep and their littermate controls were fed with high fat diet (HFD) to induce metabolic disorders. Liver ceramides content and metabolic parameters as glucose tolerance, insulin sensitivity, and hepatic glucose production were assessed. As ceramides may have impact on bile acids (BA), we investigated BA pool composition, synthesis and transport. Finally, inflammation and apoptosis were measured in the liver using western blot analysis, pro-inflammatory cytokines expression level and immunohistochemistry. Results: Despite lower expression of hepatic Sptlc2, we observed an increased concentration of hepatic ceramides, especially C16:0-ceramide. Hepatic deletion of Sptlc2 in mice was also associated with an increased neutral sphingomyelinase 2 (nSmase2) expression, and a decreased sphingomyelin content in the liver. We showed that Sptlc2{Delta}Hep mice are protected against body mass gain normally induced by HFD and displayed a decreased body fat mass. BA hydrophobicity was drastically decreased in Sptlc2{Delta}Hep mice, and was associated with a defect in lipid absorption. In addition, an important increase of tauro-murocholic acid T-MCA in BA pool composition of Sptlc2{Delta}Hep mice was associated with a downregulation of the nuclear bile acid receptor FXR target genes in ileum and liver. Sptlc2 deficiency also enhanced glucose tolerance and attenuated hepatic glucose production in an insulin-independent manner. Finally, Sptlc2 disruption promoted progressive development of hepatic fibrosis, apoptosis and inflammation in an age-related manner. Conclusion: Our data demonstrate for the first time a potential compensatory mechanism to regulate hepatic ceramides content from sphingomyelin hydrolysis. In addition, our results highlight the role of hepatic sphingolipid modulation on hepatic glucose production through bile acid composition changes.