Article Impact Level: HIGH Data Quality: STRONG Summary of Cell Metabolism. https://doi.org/10.1016/j.cmet.2024.10.016 Dr. Jivani M. Gengatharan et al.
Points
- Trans-unsaturated fatty acids (TFAs) are preferentially incorporated into sphingolipids by serine palmitoyltransferase (SPT), influencing sphingoid base synthesis and accumulating atherogenic lipoproteins.
- High-fat diets enriched with TFAs in Ldlr−/− mice accelerated VLDL secretion and sphingolipid circulation, leading to increased atherosclerosis compared to cis-unsaturated fatty acid (CFA)-enriched diets.
- Inhibition of SPT reduced circulating VLDL levels and mitigated atherosclerosis, highlighting sphingolipid metabolism as a critical factor in TFA-induced lipid dysregulation and ASCVD progression.
- Analysis of human liver tissues revealed differential regulation of SPT subunits SPTLC2 and SPTLC3, which were linked to genetic factors associated with ASCVD risk.
- Targeting SPT may provide a promising strategy to counteract TFA-induced cardiovascular risks and manage atherosclerotic disease progression.
Summary
This study investigates the role of trans-unsaturated fatty acids (TFAs) in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD), focusing on their impact on sphingolipid metabolism and lipid trafficking. The researchers found that TFAs are preferentially incorporated into sphingolipids by serine palmitoyltransferase (SPT), a key enzyme involved in sphingoid base synthesis. In vitro experiments showed that TFA-derived sphingomyelin is highly secreted from cells, suggesting that TFAs contribute to the accumulation of atherogenic lipoproteins in circulation. The study highlights how dietary TFAs influence ASCVD through their incorporation into sphingolipids.
The study further explored the effects of high-fat diets (HFDs) enriched with TFAs in Ldlr−/− mice, a model for atherosclerosis. These mice exhibited accelerated secretion of hepatic very-low-density lipoproteins (VLDL) and sphingolipids into circulation, leading to increased atherogenesis compared to mice on a cis-unsaturated fatty acid (CFA)-enriched HFD. Importantly, inhibition of SPT in these mice reduced circulating VLDL levels and mitigated the development of atherosclerosis, demonstrating the critical role of sphingolipid metabolism in TFA-induced lipid dysregulation and ASCVD progression.
Transcriptional analysis of human liver tissue revealed differential regulation of the SPT subunits SPTLC2 and SPTLC3, correlated with genetic factors linked to ASCVD. These findings underscore the significance of sphingolipid metabolism, specifically in response to dietary TFAs, as a pivotal mechanism driving the progression of ASCVD. The study suggests that targeting SPT may offer a potential therapeutic strategy to mitigate TFA-induced cardiovascular risk.
Link to the article: https://www.sciencedirect.com/science/article/abs/pii/S1550413124004121
References Gengatharan, J. M., Handzlik, M. K., Chih, Z. Y., Ruchhoeft, M. L., Secrest, P., Ashley, E. L., Green, C. R., Wallace, M., Gordts, P. L. S. M., & Metallo, C. M. (2024). Altered sphingolipid biosynthetic flux and lipoprotein trafficking contribute to trans-fat-induced atherosclerosis. Cell Metabolism. https://doi.org/10.1016/j.cmet.2024.10.016
