UC San Diego

Lipid metabolism plays a role in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD) through aberrant lipid biosynthesis and trafficking via lipoproteins. The dysregulation of these pathways occurs across various tissues and understanding tissue-specific lipid biosynthetic flux can unravel the metabolic contribution to physiological responses. Furthermore, understanding how these fluxes are regulated at the genetic level may uncover new mechanisms to be exploited as clinical targets. Sphingolipids constitute a pool of bioactive lipids that are critical in maintaining cell function and lipid homeostasis. Owing to their abundance in circulation and enrichment in lipoproteins, sphingolipids have been emerging as biomarkers of several diseases including ASCVD.

In this dissertation, we study the intersection of sphingolipid metabolism and dietary fat in the progression of ASCVD and other co-morbidities of metabolic syndrome. First, we applied mass spectrometry to quantify the metabolic flux of cis (CFAs) and trans monounsaturated fatty acids (TFAs) into sphingolipids by the initial, rate-limiting enzyme serine palmitoyltransferase (SPT). We identified novel sphingolipids synthesized from TFAs that exhibit high affinity for the sphingolipid pathway through their preferential incorporation into the long-chain base of sphingolipids and secretion from hepatocarcinoma cells. Next, we designed custom high-fat diets (HFDs) with identical macronutrient composition enriched in either CFAs or TFAs to characterize the role of sphingolipid metabolism in the progression of hepatic steatosis and atherosclerosis induced by dietary fat. Administration of a HFD enriched in TFAs to low-density lipoprotein receptor deficient (Ldlr-/-) mice accelerated liver steatosis, hepatic very-low-density lipoprotein (VLDL) secretion, and atherogenesis compared to a HFD enriched in CFAs. Mechanistically, we demonstrate that in vivo SPT inhibition mitigated these phenomena while significantly diminishing atherogenic VLDL consisting of TFA-derived polyunsaturated sphingolipids. SPT inhibition additionally remodeled the lipidome by shifting hepatic fatty acids towards phospholipids, indicating that diverting fatty acids away from SPT and downstream sphingolipids may be beneficial on these HFDs. Collectively, we elucidate a novel mechanism in which SPT flux synergizes with hepatic lipoprotein secretion to deliver atherogenic sphingolipids into circulation. Thus, we uncovered a critical metabolic link between sphingolipids and lipoprotein metabolism that can be therapeutically targeted in ASCVD in response to specific dietary fats.