Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis

Abstract

Triacylglycerols (triglycerides) (TGs) are the major storage molecules of metabolic energy and FAs in most living organisms. Excessive accumulation of TGs, however, is associated with human diseases, such as obesity, diabetes mellitus, and steatohepatitis. The final and the only committed step in the biosynthesis of TGs is catalyzed by acylCoA:diacylglycerol acyltransferase (DGAT) enzymes. The genes encoding two DGAT enzymes, DGAT1 and DGAT2, were identified in the past decade, and the use of molecular tools, including mice deficient in either enzyme, has shed light on their functions. Although DGAT enzymes are involved in TG synthesis, they have distinct protein sequences and differ in their biochemical, cellular, and physiological functions. Both enzymes may be useful as therapeutic targets for diseases. Here we review the current knowledge of DGAT enzymes, focusing on new advances since the cloning of their genes, including possible roles in human health and diseases.-Yen, C-L. E., S. J. Stone, S. Koliwad, C. Harris, and R. V. Farese, Jr. DGAT enzymes and triacylglycerol biosynthesis. J. Lipid Res. 2008. 49: 2283-2301. Supplementary key words triacylglycerolsTriacylglycerols (triglycerides) (TGs), a major type of neutral lipid, are a heterogeneous group of molecules with a glycerol backbone and three FAs attached by ester bonds. The physical and chemical properties of TG differ based on chain length and the degree to which their FAs are desaturated. TGs serve multiple important functions in living organisms. Chief among these, they are the major storage molecules of FA for energy utilization and the synthesis of membrane lipids. Because they are highly reduced and anhydrous, TGs store 6-fold more energy than the same amount of hydrated glycogen (1). In plants, TGs are a major component of seed oils, which are valuable resources for dietary consumption and industrial uses. TG from plants and microorganisms can also be used for biofuels. In animals, energy stores of TG are concentrated primarily in adipocytes, although TGs are also found prominently in myocytes, hepatocytes, enterocytes, and mammary epithelial cells. In addition to energy storage, TG synthesis in cells may protect them from the potentially toxic effects of excess FA. In the enterocytes and hepatocytes of most mammals, TGs are synthesized for the assembly and secretion of lipoproteins, which transport dietary and endogenously synthesized FA between tissues. Also, TGs in secreted lipids acts as a component of the skinʼs surface water barrier, and collections of TG in adipose tissue provide insulation for organisms.Although TGs are essential for normal physiology, the excessive accumulation of TG in human adipose tissue results in obesity and, in nonadipose tissues, is associated with organ dysfunction. For example, excessive TG deposition in skeletal muscle and the liver is associated with insulin resistance, in the liver with nonalcoholic steatohepatitis, and in the heart with cardiomyopathy (2, 3). Owing to worldwide increases in the p...

Identification of Ubxd8 protein as a sensor for unsaturated fatty acids and regulator of triglyceride synthesis

“…We then tested whether Ubxd8 mediates the other regulatory action of unsaturated FAs-namely, activation of TG synthesis. The synthesis of TGs begins with attachment of FAs to glycerol-3-phosphate, leading to the generation of diacylglycerols (DAGs), which can be converted to TGs or phospholipids (21). Diacylglycerol acyltransferases (DGATs) catalyze the final step in TG synthesis by adding the third FA molecule to DAGs (21).…”

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“…Synthesis of TAG involves the enzyme acyl CoA diacylglycerol acyltransferase (DGAT)1 that functions by catalysing a reaction with diacylglycerol and fatty acid acyl CoA substrates (61) . Overexpression of DGAT correlates with increased TAG storage in adipose tissue, skeletal muscle and liver (62)(63)(64) .…”

Not Just Fat: The Structure and Function of the Lipid Droplet

“…3; Yen et al 2008;Chang et al 2009). Hydrophobic lipid esters are likely to be deposited inside the ER membrane, although wax esters of bacterial LDs are thought to accumulate on the membrane surface (Waltermann et al 2005).…”