SPT: A new contributor to trans fatty acid-induced atherosclerosis

Atherosclerotic cardiovascular disease (ASCVD) is currently the leading cause of mortality worldwide [1,2]. Extensive basic research and clinical trials over the past several decades have demonstrated that lipids, such as cholesterol [[3], [4], [5]], sphingolipids (ceramides) [[6], [7], [8]], phospholipids including phosphatidylcholine (PC) [7], lysophosphatidylcholine (LPC) [9], and lysophosphatidic acid (LPA) [9,10], as well as the saturated fatty acid palmitic acid (PA) [11,12], are key contributors to the pathogenesis of ASCVD. Industrially produced trans-unsaturated fatty acids (TFAs) incorporated into food products are associated with ASCVD and promote its progression [13]. However, the underlying mechanism of how trans-fats are processed through downstream lipid pathways to cause their pathogenesis is largely unclear. In a recent study published in Cell Metabolism, Gengatharan et al. revealed that TFAs are selectively incorporated by serine palmitoyltransferase (SPT) to synthesize and secrete sphingolipids, and that a TFAs-enriched high-fat diet accelerated hepatic sphingolipid and VLDL secretion to promote atherosclerosis in Ldlr^-/- mice [14]. The noteworthy and captivating mechanistic finding in this study is illustrated in Fig. 1.

Fig. 1.

Pathophysiological roles of lipids in the development of ASCVD. Light blue backdrop: high levels of cholesterol [[3], [4], [5]], sphingolipids (Cer(18:0)) [7], phospholipids (PC(16:0/16:0) [7], and saturated fatty acid (palmitic acid) [11,12] in the blood are associated with adverse ASCVD outcomes and are considered pathogenic agents for ASCVD. Light red backdrop: SPTLC3 catalyzes the canonical condensation of the amino acid serine with TFAs to synthesize the LCB of sphingolipids, which subsequently expedites the progression of ASVCD [14]. SM, sphingomyelin; TFAs, trans-unsaturated fatty acids; LCB, long-chain base. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

SPT, the initial rate-limiting enzyme in sphingolipid biosynthesis, catalyzes the canonical condensation of the amino acid serine with palmitoyl-CoA to synthesize the long-chain base (LCB) of sphingolipids [15]. The researchers discovered that TFAs (such as elaidate and trans-vaccenate) are preferentially metabolized by SPT over cis-unsaturated fatty acids (CFAs) (such as oleate and cis-vaccenate) for the synthesis of sphingolipids. Further research showed that, compared with its cis isomer oleate or palmitate and stearate, elaidate induced the highest total sphingomyelin secretory flux, which could be mitigated by the SPT inhibitor myriocin. This implies that SPT activity and fatty acid structure directly impact lipid secretion.

The researchers also found that a TFA-enriched diet accelerated the progression of ASVCD. Although Ldlr ^-/- mice gained less body weight when fed the high-fat diet (HFD) supplemented with TFAs (trans-HFD) than cis-HFD, they developed more severe fatty liver and had an increased atherosclerotic lesion area within the aortic root. Furthermore, the cis-HFD diet influenced the broader lipidome. Cis-HFD treated mice exhibited atherogenic plasma, characterized by elevated levels of newly synthesized cholesterol, palmitic acid, ceramide, and sphingomyelin. More importantly, the trans-HFD diet greatly accelerated hepatic very low-density lipoprotein (VLDL) secretion. In addition, the authors identified the SPT subunit SPTLC3 as a regulator of sphingolipid homeostasis involved in this process, linking liver sphingolipid biosynthesis to lipid secretion via lipoproteins, ultimately leading to ASCVD. Consistently, application of the SPT inhibitor myriocin could alleviate the fatty liver, hyperlipidemia, and ASCVD induced by trans-HFD.

In summary, this study identified SPT as a key contributor in trans fatty acid-induced atherosclerosis and demonstrated that TFAs are preferentially utilized by SPT for the synthesis of sphingomyelin, which is subsequently secreted via sphingomyelin enriched VLDL to promote ASCVD. This SPT regulated pathway is novel when compared with the other well-known ASCVD pathways [16], opening a new door to understand ASCVD pathogenesis. As well, this study also opens new questions for future study. First, what is the ultimate role of TFAs-associated sphingomyelin after synthesis and secretion by the liver, and does it appear in atherosclerotic plaques similar to cholesterol? Secondly, can TFAs-associated sphingomyelin serve as a biomarker in the plasma of ASCVD patients? Last, but not least, this study showed that an SPT inhibitor can alleviate trans HFD-induced ASCVD in mice. The effectiveness of using an SPT inhibitor in clinical trials and their potential synergistic effects when combined with other anti-atherosclerotic therapies, such as statin [17] or manganese-enriched diets [18], will be of great interest for further investigation.

CRediT authorship contribution statement

Chengbin Li: Writing – review & editing. Junli Liu: Conceptualization, Formal analysis, Writing – original draft. Bin Liang: Visualization, Writing – original draft, Writing – review & editing.