Lipid Metabolism (Molecular Biology)

Membrane lipids belong primarily to one of three major classes of lipids: glycerolipids, sphingolipids, and sterols. These small and hydrophobic molecules (molecular weight mostly in the range of 150-2000) display a richness in structural composition that serves as the foundation for their important functions. Lipids are critical and defining components of the membrane bilayer, such that the hydrophobic acyl and alkyl groups constitute the hydrophobic interior of the membrane, whereas their head groups provide a hydrophilic interface with the aqueous environment on both sides of the membrane. The lipid composition of biological membranes varies between species, cell types, and subcellular compartments. Lipids also participate in the properties and functions of membranes, such as determining their fluidity or rigidity and possibly in determining microdomains in different membranes. In addition, lipids are of significance in ligand recognition, cell-cell interaction, and covalent modification of proteins.

Lipids also function as integral components in diverse signal transduction pathways, where the action of many extracellular agents is coupled to different enzymes of lipid metabolism. This results in the generation of specific lipid second messengers (such as diacylglycerol, platelet-activating factor, eiconasoids, and ceramide). These molecules then go on to interact with and regulate specific targets (such as protein kinase C or membrane receptors) and thus provide for signal transduction across biological membranes. It is this aspect of lipid function that has come under intense investigation, especially in the last two decades with the elucidation of several signal-activated lipases and other enzymes of lipid metabolism. As such, the study of regulation of lipid metabolism is at the heart of lipid-mediated signal transduction and cell regulation.

1. Basic Pathways of Lipid Metabolism

The metabolic pathways that regulate lipid biosynthesis and lipid composition utilize molecules that are readily available in the cell and follow simple blueprints that show significant similarity among prokaryotes, mammalian cells, and other eukaryotic systems.

1.1. Glycerolipid Metabolism

In eukaryotic cells, the initial step of phospholipid biosynthesis commences with the acylation of glycerol-3-phosphate using acetyl-CoA as the donor and resulting in the formation of 1-acyl-glycerol-3-phosphate (lysophosphatidic acid). This is further acylated to result in the formation of phosphatidic acid, which, in turn, can serve as a precursor for either diacylglycerol or CDP-diacylglycerol. CDP-diacylglycerol serves as the precursor to phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, and cardiolipin, whereas diacylglycerol can serve as the precursor for the synthesis of phosphatidylethanolamine, triacylglycerol, and phosphatidylcholine (Fig. 1). The catabolism of phosphoglycerolipids is achieved through the action of various lipases such as phospholipase C, which cleaves off the phospho head group and results in the formation of diacylglycerol. Other lipases also contribute to the breakdown of phospholipids to acetyl groups, glycerol, or glycerolphosphate.

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1.2. Sphingolipid Metabolism

The biosynthesis of sphingolipids commences with the condensation of serine and palmitoyl CoA into 3-ketodihydrosphingosine, which, in turn, is reduced to dihydrosphingosine. Dihydrosphingosine is acylated to form dihydroceramide, which is either oxidized to ceramide or incorporated into more complex sphingolipids (Fig. 2 ). The complex sphingolipids are distinguished by their specific substituents at the 1-hydroxyl position of ceramide. For example, sphingomyelin contains phosphorylcholine, whereas cerebroside contains either galactose or glucose. These glycosylated sphingolipids can serve as precursors for more complex neutral and acidic glycolipids. The catabolism of sphingolipids proceeds in a reverse and stepwise fashion through hydrolytic elimination of specific components of the head groups, eventually resulting in the formation of ceramide, which, in turn, is deacylated by the action of a ceramidase to yield sphingosine. Phosphorylation of sphingosine results in sphingosine-1-phosphate, which is a substrate for a lyase that breaks it down into phosphoethanolamine and hexadecenal.

Figure 2. The major pathway of biosynthesis of sphingolipids in eukaryotes, commencing with the condensation of serine and palmitoyl CoA.

2. Regulation of Lipid Metabolism

The regulation of intermediary lipid metabolism follows the basic and well-established principles of intermediary metabolism, with the rate-determining steps usually associated with the initial enzymes in the biosynthetic scheme (acylation of glycerolphosphate or condensation of serine and palmitoyl CoA in the biosynthesis of glycerolipids and sphingolipids, respectively).

In addition, lipid metabolism is a subject of multiple mechanisms of regulation that are critical in the determination of the levels of individual lipid precursor substrates and lipid-derived products. This is of particular significance in the myriad pathways of signal transduction. For example, phospholipases C regulate the levels of inositol trisphosphate and diacylglycerol, whereas phospholipases D regulate the levels of phosphatidic acid (see Lipases). Phospholipase A2 regulates the levels of arachidonate and, consequently, the levels of eicosanoids that function as intracellular and intercellular messengers (see Lipases). Other regulated enzymes of lipid metabolism include lipid kinases, synthases, transacylases, and other specialized enzymes.