近日，美国索尔克生物研究所Christian M. Metallo及其小组发现，改变的鞘脂生物合成通量和脂蛋白转运促进反式脂肪酸引起的动脉粥样硬化。2024年11月14日，《细胞—代谢》杂志在线发表了这项成果。

研究人员表示，膳食脂肪驱动动脉粥样硬化性心血管疾病（ASCVD）的发病机制，特别是通过循环中的胆固醇和三酰甘油丰富的脂蛋白残片。工业生产的反式不饱和脂肪酸（TFA）被加入食品供应中，显著促进ASCVD。然而，反式脂肪酸在这种关联中的分子转运机制尚不完全明了。

研究人员证明了反式脂肪酸通过丝氨酸棕榈酰转移酶（SPT）优先被纳入鞘脂中，并在体外从细胞中分泌。将富含反式脂肪酸的高脂饮食（HFD）给予Ldlr^−/−小鼠，相比富含顺式不饱和脂肪酸（CFA）的高脂饮食，加速了肝脏极低密度脂蛋白（VLDL）和鞘脂的分泌进入循环，并促进了动脉粥样硬化的发生。SPT抑制剂减轻了这些表型，并减少了富含反式脂肪酸衍生多不饱和鞘氨酸酰胆碱的循环动脉粥样硬化VLDL。

对人类肝脏的转录分析揭示了SPTLC2与SPTLC3亚单位表达的不同调控，符合人类ASCVD的遗传相关性。研究人员进一步确立了鞘脂代谢作为介导ASCVD进展的关键节点，响应特定膳食脂肪的影响。

附：英文原文

Title: Altered sphingolipid biosynthetic flux and lipoprotein trafficking contribute to trans-fat-induced atherosclerosis

Author: Jivani M. Gengatharan, Michal K. Handzlik, Zoya Y. Chih, Maureen L. Ruchhoeft, Patrick Secrest, Ethan L. Ashley, Courtney R. Green, Martina Wallace, Philip L.S.M. Gordts, Christian M. Metallo

Issue&Volume: 2024-11-14

Abstract: Dietary fat drives the pathogenesis of atherosclerotic cardiovascular disease (ASCVD), particularly through circulating cholesterol and triglyceride-rich lipoprotein remnants. Industrially produced trans-unsaturated fatty acids (TFAs) incorporated into food supplies significantly promote ASCVD. However, the molecular trafficking of TFAs responsible for this association is not well understood. Here, we demonstrate that TFAs are preferentially incorporated into sphingolipids by serine palmitoyltransferase (SPT) and secreted from cells in vitro. Administering high-fat diets (HFDs) enriched in TFAs to Ldlr/ mice accelerated hepatic very-low-density lipoprotein (VLDL) and sphingolipid secretion into circulation to promote atherogenesis compared with a cis-unsaturated fatty acid (CFA)-enriched HFD. SPT inhibition mitigated these phenotypes and reduced circulating atherogenic VLDL enriched in TFA-derived polyunsaturated sphingomyelin. Transcriptional analysis of human liver revealed distinct regulation of SPTLC2 versus SPTLC3 subunit expression, consistent with human genetic correlations in ASCVD, further establishing sphingolipid metabolism as a critical node mediating the progression of ASCVD in response to specific dietary fats.

DOI: 10.1016/j.cmet.2024.10.016

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00412-1