Disease relevance of LCAT

• Forty percent of plasma LCAT-HDL was associated with alpha(2)M; moreover, most of the LCAT in cerebrospinal fluid and in the medium of cultured human hepatoma cell line was associated with alpha(2)M [1].
• Most, if not all, of the lipoprotein changes observed are explained by the LCAT deficiency that follows IL-2-induced hepatocellular injury and cholestasis [2].
• Plasma activities of CETP and LCAT were measured in 137 male patients with moderate hypertriglyceridemia (plasma triglycerides [TGs] 200 to 500 mg/dL and LDL cholesterol < 160 mg/dL) [3].
• Plasma lipoprotein concentrations and post-heparin lipoprotein lipase, hepatic triglyceride lipase (HTGL), and lecithin:cholesterol acyltransferase (LCAT) activities were determined in 10 obese women before and after weight loss [4].
• High dose i.v. rIL-2 induces severe dyslipidemia with deficiencies of both postheparin lipases and acute LCAT deficiency [2].

Psychiatry related information on LCAT

• CONCLUSIONS: Regular moderate physical activity in patients with type 2 diabetes led to an overall increase in HL, LPL, and LCAT [5].
• In this study, postprandial changes in plasma lipids, high-density lipoprotein (HDL) composition and cholesteryl ester transfer protein (CETP) and lecithin: cholesterol acyltransferase (LCAT) activity levels were investigated in response to moderate alcohol consumption [6].
• In healthy men sleep deprivation induced a decrease in LCAT activity combined with a decline of serum cholesterol concentration; consequently, the intravascular turnover rate of cholesterol did not significantly change [7].

High impact information on LCAT

• This apoprotein serves as a cofactor for the plasma lecithin-cholesterol acyltransferase (LCAT) enzyme responsible for the formation of most cholesteryl esters in plasma, and also promotes cholesterol efflux from cells [8].
• The cholesterol in discoidal HDL is esterified by lecithin:cholesterol acyltransferase (LCAT) in a process that converts the prebeta-migrating disc into an alpha-migrating, spherical HDL [9].
• LCAT and apoE contents of CETP-D HDL-2 were markedly increased compared with control HDL-2, and increased cholesterol esterification activity resided within the apoE-HDL fraction [10].
• ApoA-I FCR was inversely associated with HDL cholesterol level (r=-0.851,P<0.01) and hLCAT activity (r=-0.816, P<0.01) [11].
• To elucidate the mechanisms responsible for this effect, 131I-HDL apoA-I kinetics were assessed in age- and sex-matched groups of rabbits (n=3 each) with high, low, or no hLCAT expression [11].

Chemical compound and disease context of LCAT

• Accordingly, full-length LCAT cDNA was cloned into pVL 1392, a high-level expression derivative of Autographa californica nuclear polyhedrosis virus (AcNPV), and the resultant plasmid was co-transfected into Trichoplusia ni insect cells (High 5 line) with a linearized viral DNA using lipofectin [12].
• This study was designed to define the role of CETP and LCAT activities on HDL-cholesterol (HDL-C) plasma levels and HDL size distribution, as determined by nondenaturating polyacrylamide gradient gel electrophoresis in 47 clinically healthy Mexican individuals without personal and family history of coronary heart disease [13].
• Effects of vitamin E and HMG-CoA reductase inhibition on cholesteryl ester transfer protein and lecithin-cholesterol acyltransferase in hypercholesterolemia [14].
• Effects of probucol and pravastatin on plasma lipids, activities of postheparin lipoprotein lipase, and lecithin cholesterol acyltransferase and apo A-I containing lipoproteins with and without apo A-II in patients with moderate hypercholesterolemia [15].
• The effect of high dose medroxyprogesterone acetate (MPA) on serum lipids, on adipose tissue lipoprotein lipase (LPL) and serum lecithin cholesterol acyltransferase activities were studied in 15 postmenopausal patients with endometrial cancer [16].

Biological context of LCAT

• Our data indicate that the regions adjacent to Thr123 and Thr347 of LCAT may play an important role in HDL cholesterol esterification, suggesting that these regions may contain a portion of the LCAT binding domain(s) for HDL [17].
• LCAT activity and LCAT mass in 23 genotypic heterozygotes were approximately half normal and clearly distinct from those of 20 unaffected family members [18].
• In the homozygous patients no obvious relationship between residual LCAT activity and the clinical phenotype was seen [18].
• DNA sequence analysis of the proband's LCAT gene revealed two separate C to T transitions resulting in the substitution of Thr123 with Ile and Thr347 with Met [17].
• To assess the effects of increased plasma levels of LCAT, four lines of transgenic mice were created expressing a Hu LCAT gene driven by either its natural or the mouse albumin enhancer promoter [19].

Anatomical context of LCAT

• These findings led us to postulate that poor activation of LCAT in interstitial fluid may result from a change in conformation in apoA-I [20].
• The 1550 base LCAT mRNA can be detected in liver and HepG2 (hepatocyte) cells, but not in small intestine, spleen, pancreas, placenta or adrenal tissue [21].
• Transient expression of the mutant LCAT(Fin) cDNA in COS cells disclosed markedly diminished LCAT enzyme activity [22].
• To determine whether alpha-LpA-I generated by fibroblasts is a good substrate for LCAT, isolated alpha-LpA-I as well as reconstituted HDL [r(HDL)] was reacted with LCAT [23].
• Postprandial chylomicrons: potent vehicles for transporting cholesterol from endogenous LDL+HDL and cell membranes to the liver via LCAT and CETP [24].

Associations of LCAT with chemical compounds

• The classical inhibitor of LCAT activity, 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), which strongly (89%) inhibited the native enzyme, had partial (45%) inhibitory activity with mutant enzyme species containing a single -SH residue, while the double mutant was not significantly inhibited by DTNB [25].
• This result is not consistent with a catalytic role for LCAT free cysteine residues [25].
• In order to clarify the role of sphingomyelin in the regulation of the LCAT reaction and its effects on the structure of apolipoprotein A-I, we prepared reconstituted HDL (rHDL) containing egg phosphatidylcholine, cholesterol, apolipoprotein A-I, and up to 22 mol % sphingomyelin [26].
• Mutants deficient in their ability to activate LCAT displayed alterations in liposome and HDL binding, compared with WT as determined by density gradient ultracentrifugation analysis of the culture medium [27].
• To elucidate further the conformation of human apolipoprotein A-I (apoA-I) in lipid-bound states and its effect on the reaction with lecithin cholesterol acyltransferase (LCAT), we prepared reconstituted HDL (rHDL) particles from a reaction mixture containing dipalmitoylphosphatidylcholine/cholesterol/apoA-I in the molar ratios of 150:7.5:1 [28].

Physical interactions of LCAT

• LCAT has been reported to be involved in reverse-cholesterol transport and PON to be preventive for lipid peroxidation of low-density lipoprotein in vitro [29].
• From our results we speculate that apolipoprotein D may have some stabilizing effect on the enzyme LCAT [30].
• DMPC - or egg yolk phosphatidylcholine - cholesterol-[4-14C]cholesterol-serum amyloid A complexes per se did not stimulate LCAT activity significantly [31].

Regulatory relationships of LCAT

• Furthermore, the finding supports the possibility that the LRP receptor can act in vivo to mediate clearance of the LCAT-alpha(2)M complex and may significantly influence the bioavailability of LCAT [1].
• Using transfected HepG2 cells, results indicate that treatment with IL-6 induced a 2.5-fold activation of full-length LCAT promoter activity [32].
• The results suggest that Hpt inhibits the reverse transport of cholesterol by preventing ApoA1 stimulation of the LCAT activity [33].
• Our experiments demonstrate that LCAT promotes HDL3/HDL2 interconversion in native serum irrespective of the presence or absence of triglyceride-rich lipoproteins and lipoprotein lipase [34].
• Apo-E was found to be 18% as effective as apo-A-I in activating purified human lecithin cholesterol acyltransferase [35].

Other interactions of LCAT

• Evidence for linkage was observed at the MnSOD (P=.02), CETP/LCAT (P=.03), and apolipoprotein AI-CIII-AIV loci (P=.005) but not at the LDLR locus [36].
• These data show that carriers of an apoA-I mutation exhibit the most pronounced accelerated atherosclerosis compared with those carrying mutations in ABCA1 and LCAT [37].
• By stepwise regression analysis CETP appeared to contribute 15.2% and LCAT 9.8% to variation in HDL-cholesterol levels [3].
• In conclusion, we have identified a novel LCAT gene Gly230Arg mutation (LCAT[Fin]), which, together with the LPL Asn291Ser mutation, represents a relatively common genetic cause of diminishing HDL-C levels, at least among Finns [22].
• ApoA-I enters the plasma as a component of discoidal particles, which are remodeled into spherical (A-I)HDL by LCAT [38].

Analytical, diagnostic and therapeutic context of LCAT

• The mass of LCAT secreted, determined by immunoassay, did not differ in the native and mutant species [25].
• Electron microscopy of the proteoliposome LCAT substrate generated by WT and mutant apoA-I forms showed that the carboxyl-terminal deletion mutants which displayed aberrant binding to HDL also displayed reduced ability to convert the spherical lecithin-cholesterol vesicles into discs compared with WT [27].
• Plasma lecithin-cholesterol acyltransferase (LCAT) activity, lipoprotein composition, and lipoprotein concentrations were measured in 21 children with kwashiorkor before (day 1), during (day 10), and after treatment (day 30) [39].
• Moreover, LCAT's antiatherogenic effect requires only a single functional LDLr allele, identifying LCAT as an attractive gene therapy candidate for the majority of dyslipoproteinemic patients [40].
• Since recent studies have shown that a tryptophan residue in the putative interfacial domain (Trp(61)) is critical for the activity, we determined the possible role of this residue in the oxidative susceptibility and substrate specificity of LCAT by site-directed mutagenesis [41].

References