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Metabolism of Acylglycerols & Sphingolipids
Kathleen M. Botham, PhD, DSc & Peter A. Mayes, PhD, DSc
OBJECTIVES
After studying this chapter, you should be able to:
Appreciate that the catabolism of triacylglycerols involves hydrolysis by a lipase to free fatty acids and glycerol and indicate the fate of these metabolites.
Understand that glycerol-3-phosphate is the substrate for the formation of both triacylglycerols and phosphoglycerols and that a branch point at phosphatidate leads to the synthesis of inositol phospholipids and cardiolipin via one branch and triacylglycerols and other phospholipids via the second branch.
Explain that plasmalogens and platelet activating factor (PAF) are formed by a complex pathway starting from dihydroxyacetone phosphate.
Illustrate the role of various phospholipases in the degradation and remodeling of phospholipids.
Appreciate that ceramide is produced from the amino acid serine and is the precursor from which all sphingolipids are formed.
Indicate how sphingomyelin and glycosphingolipids are produced by reacting ceramide with phosphatidylcholine (with the release of diacylglycerol) or sugar residue(s), respectively.
Identify examples of disease processes caused by defects in phospholipid or sphingolipid synthesis or breakdown.
BIOMEDICAL IMPORTANCE
Acylglycerols constitute the majority of lipids in the body. Triacylglycerols are the major lipids in fat deposits and in food, and their roles in lipid transport and storage and in various diseases such as obesity, diabetes, and hyperlipoproteinemia will be described in subsequent chapters. The amphipathic nature of phospholipids and sphingolipids makes them ideally suitable as the main lipid component of cell membranes. Phospholipids also take part in the metabolism of many other lipids. Some phospholipids have specialized functions; eg, dipalmitoyl lecithin is a major component of lung surfactant, which is lacking in respiratory distress syndrome of the newborn. Inositol phospholipids in the cell membrane act as precursors of hormone second messengers, and platelet-activating factor is an alkylphospholipid. Glycosphingolipids, containing sphingosine and sugar residues as well as fatty acid that are found in the outer leaflet of the plasma membrane with their oligosaccharide chains facing outward, form part of the glycocalyx of the cell surface and are important (1) in cell adhesion and cell recognition, (2) as receptors for bacterial toxins (eg, the toxin that causes cholera), and (3) as ABO blood group substances. A dozen or so glycolipid storage diseases have been described (eg, Gaucher’s disease and Tay-Sachs disease), each due to a genetic defect in the pathway for glycolipid degradation in the lysosomes.
HYDROLYSIS INITIATES CATABOLISM OF TRIACYLGLYCEROLS
Triacylglycerols must be hydrolyzed by a lipase to their constituent fatty acids and glycerol before further catabolism can proceed. Much of this hydrolysis (lipolysis) occurs in adipose tissue with release of free fatty acids into the plasma, where they are found combined with serum albumin (Figure 25–7). This is followed by free fatty acid uptake into tissues (including liver, heart, kidney, muscle, lung, testis, and adipose tissue, but not readily by brain), where they are oxidized or re-esterified. The utilization of glycerol depends upon whether such tissues have the enzyme glycerol kinase, which is found in significant amounts in liver, kidney, intestine, brown adipose tissue, and the lactating mammary gland.
TRIACYLGLYCEROLS & PHOSPHOGLYCEROLS ARE FORMED BY ACYLATION OF TRIOSE PHOSPHATES
The major pathways of triacylglycerol and phosphoglycerol biosynthesis are outlined in Figure 24–1. Important substances such as triacylglycerols, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and cardiolipin, a constituent of mitochondrial membranes, are formed from glycerol-3-phosphate. Significant branch points in the pathway occur at the phosphatidate and diacylglycerol steps. Phosphoglycerols containing an ether link (—C—O—C—), the best known of which are plasmalogens and platelet-activating factor (PAF), are derived from dihydroxyacetone phosphate. Glycerol 3-phosphate and dihydroxyacetone phosphate are intermediates in glycolysis, making a very important connection between carbohydrate and lipid metabolism (see Chapter 16).
FIGURE 24–1 Overview of acylglycerol biosynthesis. (PAF, platelet-activating factor.)
Phosphatidate Is the Common Precursor in the Biosynthesis of Triacylglycerols, Many Phosphoglycerols, & Cardiolipin
Both glycerol and fatty acids must be activated by ATP before they can be incorporated into acylglycerols. Glycerol kinase catalyzes the activation of glycerol to sn-glycerol 3-phosphate. If the activity of this enzyme is absent or low, as in muscle or adipose tissue, most of the glycerol 3-phosphate is formed from dihydroxyacetone phosphate by glycerol-3-phosphate dehydrogenase (Figure 24–2).
FIGURE 24–2 Biosynthesis of triacylglycerol and phospholipids. (
, Monoacylglycerol pathway;
, glycerol phosphate pathway.) Phosphatidylethanolamine may be formed from ethanolamine by a pathway similar to that shown for the formation of phosphatidylcholine from choline.
Biosynthesis of Triacylglycerols
Two molecules of acyl-CoA, formed by the activation of fatty acids by acyl-CoA synthetase (Chapter 22), combine with glycerol 3-phosphate to form phosphatidate (1,2-diacylglycerol phosphate). This takes place in two stages, catalyzed by glycerol-3-phosphate acyltransferase and 1-acylglycerol-3-phosphate acyltransferase. Phosphatidate is converted by phosphatidate phosphohydrolase and diacylglycerol acyltransferase (DGAT) to 1,2-diacylglycerol and then triacylglycerol. DGAT catalyzes the only step specific for triacylglycerol synthesis and is thought to be rate limiting in most circumstances. In intestinal mucosa, monoacylglycerol acyltransferase converts monoacylglycerol to 1,2-diacylglycerol in the monoacylglycerol pathway.
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