Role of LCAT in HDL Remodeling: Investigation of LCAT Deficiency States

Authors: ASZTALOS, BELA - TUFTS UNIVERSITY; Schaefer, Ernst; HORVATH, KAITLIN - TUFTS UNIVERSITY; YAMASHITA, SHUZUYA - OSAKA UNIVERSITY; MILLER, MICHAEL - UNIVERSITY OF MARYLAND; FRANCESCHINI, GUIDO - UNIVERSITY OF MILAN; CALABRESI, LAURA - UNIVERSITY OF MILAN

Submitted to: Journal of Lipid Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/1/2006
Publication Date: 12/20/2006
Citation: Asztalos, B.F., Schaefer, E., Horvath, K.V., Yamashita, S., Miller, M., Franceschini, G., Calabresi, L. 2006. Role of LCAT in HDL Remodeling: Investigation of LCAT Deficiency States. Journal of Lipid Research. 48:592-599.

Interpretive Summary: Cholesterol in the blood is carried on two major particles known as low density lipoproteins or LDL and high density lipoproteins or HDL. High LDL cholesterol over 160 mg/dl and low HDL cholesterol below 40 mg/dl are important risk factors for heart disease. A genetic disorder characterized by an inabilty to add a fatty acid to cholesterol known as cholesterol esterification results in low and abnormal HDL. Our purpose was to characterize these HDL particles in the blood of affected and unaffected people. Our data indicate that tose people that lack the abilty to esterify cholesterol, have low HDL due to loss of large beneficial HDL particles. This finding puts these subjects at increased of heart disease, and allows for a better way to diagnose them.

Technical Abstract: To better understand the role of LCAT in HDL metabolism, we compared HDL subpopulations in subjects with homozygous (n 5 11) and heterozygous (n 5 11) LCAT deficiency with controls (n 5 22). Distribution and concentrations of apolipoprotein A-I (apoA-I)-, apoA-II-, apoA-IV-, apoC-I-, apoC-III-, and apoE-containing HDL subpopulations were assessed. Compared with controls, homozygotes and heterozygotes had lower LCAT masses (277% and 213%), and LCAT activities (299% and 239%), respectively. In homozygotes, the majority of apoA-I was found in small, disc-shaped, poorly lipidated preb-1 and a-4 HDL particles, and some apoA-I was found in larger, lipid poor, discoidal HDL particles with a-mobility. No apoC-I containing HDL was noted, and all apoA-II and apoC-III was detected in lipid-poor, preb-mobility particles. ApoE containing particles were more disperse than normal. ApoAIV-containing particles were normal. Heterozygotes had profiles similar to controls, except that apoC-III was found only in small HDL with preb-mobility. Our data are consistent with the concepts that LCAT activity: 1) is essential for developing large, spherical, apoA-I-containing HDL and for the formation of normal-sized apoC-I and apoC-III HDL; and 2) has little affect on the conversion of preb-1into a-4 HDL, only slight effects on apoE HDL, and no effect on apoA-IVHDL particles. LCAT is a 416 amino acid protein that binds to lipoproteinsor is present in lipid-free form in plasma and is secreted by the liver in humans (1). LCAT synthesizes the majority of cholesteryl esters in plasma by transferring a fatty acid from lecithin (phosphatidyl choline) to the 3-hydroxyl group of cholesterol. It is generally believed that LCAT maintains the unesterified cholesterol gradient between peripheral cells and HDL. Efflux of free cholesterol (FC) from cells occurs by a passive diffusion of FC between cellular membranes and acceptors and by mechanisms facilitated by scavenger receptor type B-I (SR-BI) and ABCs. In the presence of LCAT, the bi-directional movement of cholesterol between cells and HDL results in net cholesterol efflux. Therefore, LCAT plays acentral role in the initial steps of reverse cholesterol transport. LCAT is activated primarily by apolipoprotein A-I (apoA-I), but can also be activated by apoA-IV, apoC-I, and apoE (4, 5). Both the binding and activation of LCAT on the surface of HDL are essential for esterification of FC and accumulation of cholesteryl esters in the core of HDL. Familial LCAT deficiency (FLD) is characterized by the absence of LCAT activity and reduced HDL cholesterol (HDL-C) level in plasma. In affected individuals, LCAT is either absent or present but inactive in plasma (6). LCAT has two distinct substrates: HDL and LDL. LCAT activity on HDL is called a-activity, and LCAT activity on LDL is called b-activity (7, 8). Lack of a-LCAT activity causes fish eye disease (FED). Homozygous subjects with FLD have corneal opacification, anemia, proteinuria, hematuria, and ultimately, renal failure, often requiring kidney transplantation (9). FED subjects have no clinical manifestation other than an age-dependent corneal opacification. Although it is not clear whether LCAT deficiency is directly linked to premature coronary artery disease (CAD), increased risk for CAD has been reported in some patients (9). Data obtained from cholesterol-fed human-LCAT transgenic rabbits indicated that HDL-C increased due to decreased catabolism of larger HDL particles, suggesting that the size of HDL may modulate the selective HDL-C uptake by the liver (10). In human-LCAT transgenic mice, the liver uptake of HDL was reduced by 41%,resulting in a substantial increase of large HDL particlesthat might be atherogenic (11) due to the fact that mice lack cholesteryl ester transfer protein (CETP) and that continued increase of cholesteryl ester in HDL by high levels