Sphingolipids: major regulators of lipid metabolism

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Abstract
Sphingolipids and their metabolites regulate a great variety of cellular processes. Recent findings implicate sphingolipids in the regulation of lipid synthesis, lipoprotein metabolism and the development of atherosclerosis. Sphingolipid synthesis correlates with the regulation of the sterol-regulatory element-binding proteins - key transcription factors of genes of lipid metabolism. Inhibition of sphingolipid synthesis decreases synthesis of genes regulated by sterol regulatory element-binding protein, such as the rate-limiting enzymes of fatty acid and cholesterol synthesis as well as fatty-acyl-CoA synthases, important in the synthesis of phospholipids. In animal models, inhibition of sphingolipid synthesis correlates with decreased atherosclerotic lesions and a decreased susceptibility of lipoproteins to aggregate--a key mechanism in the development of the atherosclerotic lesion. The demonstration that ceramide and glucosylceramide (metabolites of sphingolipid synthesis) affect cholesterol efflux and mechanisms that regulate plasma high-density lipoprotein concentrations is further evidence for a role of sphingolipids in the regulation of lipid homeostasis. Direct mechanisms of how sphingolipid synthesis regulates lipid synthesis are currently unknown. The recent identification of key proteins of synthesis and specific transport proteins that regulate sphingolipid synthesis, however, is expected to contribute to the understanding about the interdependent regulation of sphingolipid and lipid metabolism. Emerging data strongly suggest a role of sphingolipid synthesis in the regulation of transcription factors and regulatory proteins that control cellular lipid homeostasis.