Sphingolipid synthetic pathways are major regulators of lipid homeostasis

This chapter focuses on the role of sphingolipids in the regulation of sterol-regulatory element binding protein (SREBP) dependent lipid synthesis and ATP-binding cassette protein ABCA1 and ABCG1 mediated lipid efflux, key regulators of cellular lipid homeostasis. Sphingolipid synthesis activates SREBPs independently of whether sphingolipid synthesis occurs through recycling or de novo pathways. SREBPs are major transcription factors of lipid metabolism that regulate more than 30 genes of cholesterol, fatty acid and phospholipid synthetic enzymes and they required NADPH cofactors. SREBPs are downstream of sphingolipid synthesis and do not regulate activity of sphingolipid synthetic enzymes. Cells that cannot synthesize sphingolipids fail to increase SREBP in response to lipid depletion. Similar mechanisms are found in D. melanogaster in which SREBP activity depends on expression of a ceramide synthase analog. SREBP is inhibited by its end products cholesterol and unsaturated fatty acids. Ceramide decreases SREBP by inhibiting sphingolipid synthesis. Molecular mechanisms of regulation are related to the effect of sphingolipids on intracellular trafficking but are overall not clear. Several groups have investigated the effect of sphingolipids in the regulation of cholesterol efflux receptors ABCA1 and ABCG1, major regulators of plasma high-density lipoprotein (HDL) concentration, an important anti-atherogenic lipoprotein. Data indicate an inverse relationship between sphingolipid de novo synthesis and cholesterol efflux. Inhibition of sphingolipid de-novo synthesis increases ABCA1 mediated cholesterol efflux independent of sphingomyelin. Potential mechanisms include the physical interaction of subunit 1 of serine-palmitoyl transferase (SPT), the rate limiting enzyme of de-novo sphingolipid synthesis, with ABCA1. ABCG1 mediated efflux, in contrast, is dependent on sphingomyelin mass. Animal studies support the findings made in cultured cells. Inhibition of sphingolipid de novo synthesis increases anti-atherogenic lipoproteins and decreases atherosclerosis in mouse models. Together, manipulation of sphingolipid synthetic pathways is a potentially promising therapeutic target for treatment of low-HDL dyslipidemia and atherosclerosis.