Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewLecithin cholesterol acyltransferase
Introduction
Cholesterol transport in blood is carried out by low- and high-density lipoproteins (HDL). Low-density lipoproteins (LDL) transport cholesterol from the liver to peripheral tissues, whereas HDL transports cholesterol from peripheral tissues to the liver for excretion as bile salts and to steroidogenic tissues for synthesis of steroid hormones. This ‘reverse transport’ of cholesterol by HDL is intimately connected with the actions of a plasma enzyme, lecithin cholesterol acyltransferase (LCAT), that converts cholesterol into long-chain cholesteryl esters on HDL and promotes cholesterol movement from tissues into HDL [1], [2]. In severe LCAT deficiencies, cholesterol and cholesteryl esters accumulate in tissues, and unesterified cholesterol levels increase in blood cell membranes and in lipoproteins causing perturbations in their structures and functions. Thus, LCAT is a key enzyme in maintaining cholesterol homeostasis and regulating its transport in blood.
Lecithin cholesterol acyltransferase was identified as a unique plasma enzyme in 1962 by Glomset [3]. Subsequent work revealed that human LCAT is a glycoprotein with a polypeptide mass of 49 kDa, augmented to around 60 kDa by a 20% carbohydrate mass. Its secondary structure contains β-sheet and α-helical elements, and a large proportion of loops. While the three-dimensional structure of LCAT is not yet known, a topological computer model of the secondary structure core of the enzyme has been constructed [4]. The model is based on structural and functional homology of LCAT with members of the lipase family that are known to have an α/β hydrolase fold [5].
Most of LCAT is synthesized by the liver and circulates in blood reversibly bound to lipoproteins. Some LCAT is also produced in the brain, and is present in very low concentrations in cerebrospinal fluid. The role of LCAT in the brain is not yet understood. In blood, LCAT preferentially binds to HDL, is activated by the major protein component of HDL, apolipoprotein A-I (apoA-I), and converts cholesterol and phosphatidylcholines (lecithins) of HDL into cholesteryl esters and lysophosphatidylcholines by a transesterification reaction involving a Asp–His–Ser catalytic triad. The formation and accumulation of cholesteryl esters in the core of HDL not only removes cholesterol from the surface of HDL and promotes flux of cholesterol from cell membranes into HDL, but also leads to morphological changes in HDL. Nascent discoidal HDL build up a cholesteryl ester core and become spherical HDL that grow in size as more cholesteryl esters accumulate. In subsequent transfers, catalyzed by cholesteryl ester transfer protein (CETP), excess cholesteryl esters are transferred from HDL to LDL and VLDL. In fact, most of the cholesterol in lipoproteins circulates as cholesteryl esters that are produced by LCAT.
Since the mid-1990s, studies of transgenic animals overexpressing human LCAT have confirmed the importance of this enzyme in cholesterol homeostasis and have suggested the LCAT gene as a target of therapeutic intervention for preventing or reversing atherosclerosis.
This review article focuses on recent advances in research on the structure of LCAT, the interfacial reaction of LCAT with lipoproteins, and the expression of the human LCAT gene in humans and experimental animals.
Section snippets
Linear sequence
The gene and cDNA for human LCAT were first cloned and sequenced in 1986 by McLean and colleagues [6], and chemical sequencing of LCAT was completed in 1987 by Yang et al. [7]. The single polypeptide chain of 416 amino acid residues (see Fig. 1) is more hydrophobic than plasma apolipoproteins, but somewhat more hydrophilic than integral membrane proteins, as expected for a water soluble enzyme that, in the course of its catalytic action, binds reversibly to lipid surfaces and uses lipid
LCAT reactions and substrates
The most important physiologic reaction of LCAT is the conversion of cholesterol and phosphatidylcholine (PC) (lecithin) to cholesteryl ester and lysophosphatidylcholine (lysoPC). As shown in Fig. 4, the reaction takes place in multiple steps on the surface of HDL involving interfacial binding, activation, PC binding, acyl enzyme formation, release of lysoPC, cholesterol binding, and release of cholesteryl ester and enzyme. While the forward reaction direction is usually favored, there is
LCAT gene
A single copy of the human LCAT gene is found on chromosome 16 (region 16q 22). The 4.5 kb gene contains six exons (1.5 kb of coding sequence) [6], [72]. The promoter, about 100 bp upstream of the first exon, contains a TATA box, two Sp1 binding sites and an LFAI motif [73]. The mRNA for LCAT is present in substantial levels in the liver and, in much smaller amounts, in the brain of humans, rabbits and mice [74], [75]. In addition to the translated sequence, human LCAT mRNA contains a 22 base
Concluding remarks
Advances in the understanding of the properties and functions of LCAT have been quite extensive in the last decade. The structural organization of LCAT is beginning to emerge from modeling work; the nature of its glycan components has been examined; diverse reactions and substrates of LCAT have been described in plasma and in pure systems; some of the steps of the main enzymatic reaction on lipid surfaces have been investigated by new quantitative approaches; and structure–function
Acknowledgments
I would like to express my gratitude to Dr Frank Peelman and Dr Maryvonne Rosseneu for permission to use their 3-dimensional model of LCAT in Fig. 3; to Jeff Kosman for critically reading the manuscript; and to Jeanne Danes for assembling the reference list. Research from my laboratory on LCAT has been supported for many years by NIH Grant HL-29939 and by the American Heart Association (Illinois Affiliate) predoctoral and postdoctoral fellowships to L. Jin, S. Adimoolam, and J. Kosman.
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