Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

Sphingolipids are a diverse group of lipids that have essential cellular roles as structural components of membranes and as potent signaling molecules. In recent years, a detailed picture has emerged of the basic biochemistry of sphingolipids—from their initial synthesis in the endoplasmic reticulum (ER), to their elaboration into complex glycosphingolipids, to their turnover and degradation. However, our understanding of how sphingolipid metabolism is regulated in response to metabolic demand and physiologic cues remains incomplete. Here I discuss new insights into the mechanisms that ensure sphingolipid homeostasis, with an emphasis on the ER as a critical regulatory site in sphingolipid metabolism. In particular, Orm family proteins have recently emerged as key ER-localized mediators of sphingolipid homeostasis. A detailed understanding of how cells sense and control sphingolipid production promises to provide key insights into membrane function in health and disease.Eukaryotic cell membranes maintain a complex and tightly regulated complement of lipids and proteins that are essential for their function. These lipids can be divided into three broad classes—sterols, glycerolipids, and sphingolipids—on the basis of their distinct chemical structures and dedicated enzymatic machineries (Fig. 1A–C). Sphingolipids typically represent ∼10%–20% of cellular lipids and have essential functions arising both from their effects on the physical properties of membranes and from their roles as signaling molecules (van Meer et al. 2008). Additionally, the activities of many transmembrane and peripheral membrane proteins are dependent on their close association with sphingolipids (Lingwood and Simons 2010). Over recent years, sphingolipids have been shown to participate in an increasingly wide range of biological processes that includes secretion, endocytosis, chemotaxis, neurotransmission, angiogenesis, and inflammation (Hannun and Obeid 2008; Lingwood and Simons 2010; Lippincott-Schwartz and Phair 2010; Blaho and Hla 2011; Lingwood 2011).Open in a separate windowFigure 1.Structures of sphingolipids and other cellular lipids. (A–C) Representative structures of (A) sphingolipids, (B) glycerolipids, and (C) sterols. (D) Formation of sphingolipids from key building blocks, long chain bases (LCBs), and coenzyme A-linked fatty acids (FA-CoAs) that often have a very long acyl chain (VLCFA-CoA). Serine palmitoyltransferase (SPT) produces the LCB intermediate 3-keto-dihydrosphingosine, which is then reduced to yield LCBs that are used by ceramide synthase (CerS) to form ceramides. Sphingolipid structural diversity arises from (a) headgroup modifications including phosphorylation, glycosylation, or phosphocholine addition, (b) LCB hydroxylation, (c) LCB desaturation, (d) variability in the length of the N-linked acyl chain, and (e) desaturation of the N-linked acyl chain.The focus of this article is the variety of regulatory mechanisms that cells use to ensure sphingolipid homeostasis. This task requires balancing sphingolipid levels in conjunction with sterols and glycerolipids and adapting sphingolipid metabolism in response to physiological cues and external stresses. A need for tight regulatory control is further highlighted by the potent signaling activities of many sphingolipid biosynthetic intermediates such as sphingosines and ceramides (Hannun and Obeid 2008; Fyrst and Saba 2010; Blaho and Hla 2011). Additionally, because most sphingolipids cannot move freely between different organelles, cells must regulate multiple intracellular pools of sphingolipids as well as lipid transport between these sites.It is noteworthy that, despite great progress in defining the enzymes that carry out sphingolipid synthesis and degradation, how cells achieve sphingolipid homeostasis remains poorly understood. In this article, I will describe recent progress in the field and highlight outstanding questions. In particular, I will discuss the emergence of the endoplasmic reticulum (ER) as a key site for sphingolipid homeostasis. Several critical enzymes in sphingolipid metabolism are found in the ER, and recent studies have identified a mechanism for matching sphingolipid production to metabolic demand that depends on the ER-localized Orm family of proteins (Breslow et al. 2010). Although many details of Orm protein function remain to be discovered, Orm proteins provide a valuable model for understanding how cells sense sphingolipids and dynamically regulate sphingolipid metabolism.