Disease relevance of Lcat

• Complete lecithin cholesterol acyltransferase (LCAT) deficiency is a rare genetic cause of extreme reduction in high density lipoproteins and there is a high prevalence of chronic renal dysfunction that may progress to renal failure [1].
• Lecithin-cholesterol acyltransferase deficiency is frequently associated with hypertriglyceridemia (HTG) in animal models and humans [2].
• Efficient coexpression and secretion of anti-atherogenic human apolipoprotein AI and lecithin-cholesterol acyltransferase by cultured muscle cells using adeno-associated virus plasmid vectors [3].
• These findings indicate that the use of polycistronic retrovirus vectors to genetically modify myoblasts, which can be transplanted back into skeletal muscle, might be a safe and feasible strategy to express human apo A-I and LCAT and hence have therapeutic potential to regress atherosclerotic lesions [4].
• Indeed, both apo A-I and LCAT genes have been identified as therapeutic targets to prevent or limit atherogenesis [4].

High impact information on Lcat

• This is most likely due to reduced activity of the HDL-catabolic enzyme hepatic lipase (Lipc) and increased expression of HDL-cholesterol esterifying enzyme lecithin:cholesterol acyl transferase (Lcat) [5].
• Previous in vitro studies suggest the vesicular lipoprotein X (LpX) particles commonly seen in LCAT-deficient plasmas may be causative [1].
• Hypertriglyceridemia in lecithin-cholesterol acyltransferase-deficient mice is associated with hepatic overproduction of triglycerides, increased lipogenesis, and improved glucose tolerance [2].
• Enhancement of scavenger receptor class B type I-mediated selective cholesteryl ester uptake from apoA-I(-/-) high density lipoprotein (HDL) by apolipoprotein A-I requires HDL reorganization by lecithin cholesterol acyltransferase [6].
• Self-association, alpha-helicity, cholesterol efflux, and lecithin-cholesterol acyltransferase activity of the recombinant proteins were also assessed [7].

Chemical compound and disease context of Lcat

• This would suggest that hypertriglyceridemia and hypercholesterolemia result from inhibition of LPL and C7alphaH, respectively, while the biologic activity of CETP and LCAT are indirectly increased to compensate for the increased cholesterol burden [8].

Biological context of Lcat

• The adrenals of the male Lcat (-/-) mice were severely depleted of lipid stores, which was associated with a 2-fold up-regulation of the adrenal SR-BI mRNA [9].
• LDLs (1 microg FC) from each genotype were incubated with purified recombinant mouse LCAT; LDL particles from B6 and apoA-I(-)(/)(-) plasma were much better substrates for CE formation (5.7% and 6.3% CE formed/30 min, respectively) than those from apoE(-)(/)(-) and apoE(-)(/)(-) apoA-I(-)(/)(-) plasma (1.2% and 1.1% CE formed/30 min) [10].
• Cholesterol esterification rate (CER) in apoA-I(-)(/)(-) apoE(-)(/)(-) mouse plasma was <7% that of C57Bl/6 (B6) mouse plasma, even though apoA-I(-)(/)(-) apoE(-)(/)(-) plasma retained (1)/(3) the amount of B6 LCAT activity [10].
• Endogenous LCAT activity, measured as the decrease in plasma free cholesterol after a 1 h incubation at 37 degrees C, was ordered: 44 +/- 3 (normal) > 21 +/- 2 (heterozygotes) > 5 +/- 1 (homozygotes) nmol CE formed/h per ml plasma [11].
• These studies indicate that ectopic overexpression of apoAI and LCAT in muscle tissue using AAV-based plasmid vectors might provide a feasible anti-atherogenic strategy in vivo [3].

Anatomical context of Lcat

• Additionally, cells transfected with a bicistronic AAV-based vector containing an internal ribosome entry site (IRES) efficiently expressed both apoAI and LCAT simultaneously [3].
• Moreover, transduced C2C12 mouse myoblasts maintained the ability for heterologous expression of human LCAT and apo A-I even after differentiation into myotubes [4].
• Among the groups, there was no significant difference in the tissue cholesterol levels in other organs, such as the liver, spleen, thymus, brain, erythrocytes, thyroid gland, testis, and aorta, resulting from either LCAT deficiency or probucol [12].
• Tissue cholesterol content was lower in the adrenal glands and ovaries in the LCAT-deficient mice and in the probucol-treated mice, suggesting that HDL is a main cholesterol provider for these organs [12].

Associations of Lcat with chemical compounds

• In C. pneumoniae infected mice, a minor change in triglyceride (corrected p-value 0.020) levels was observed 9 days post-infection (p.i.). LCAT activity declined remarkably, and the lowest activities were measured on day 9 p.i. (67% from the baseline value) [13].
• Stably-transduced clones of C2C12 cells were selected by neomycin (G418) resistance and continued to efficiently express human LCAT for 60 days [4].
• LCAT deficiency and probucol markedly decreased plasma HDL, and the effects were synergistic [12].
• Feeding to mice of both basal as well as high sucrose diet led to increased levels of plasma triglycerides, which was associated with increased lecithin-cholesterol acyltransferase activity [14].
• Human lecithin-cholesterol acyltransferase (LCAT) preferentially attacks sn-1 position of 16:0-20:4 phosphatidylcholine (PC), producing more 16:0 cholesteryl ester (CE) than 20:4 CE [15].

Regulatory relationships of Lcat

• CONCLUSIONS: Plasma CETP is posttranscriptionally downregulated in the lcat(-/-) mice, presumably by its extremely low HDL [16].

Other interactions of Lcat

• Compared to Lcat (+/+) mice, HDL-cholesterol is reduced 94% and apoA-I, 90%, in Lcat (-/-) mice; this reduction in HDL is paralleled by a 71% decrease in PAF-AH activity and in a 58% decrease in PON activity [17].
• In contrast, a 220% increase in the formation of mature HDL was observed when ABCA1 function and LCAT activities were restored [18].

Analytical, diagnostic and therapeutic context of Lcat

• We studied the effect of plasma apoA-I concentration on LCAT activation, using normal, heterozygous or homozygous apoA-I-deficient mice made by gene targeting [11].
• Three human apoA-I-specific monoclonal antibodies were found to inhibit LCAT activation in vitro in a manner directly proportional to their ability to bind to apoA-I-proteoliposomes in fluid phase immunoassays [19].

References