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Effect of recombinant human lecithin cholesterol acyltransferase infusion on lipoprotein metabolism in mice.

ABSTRACT: Lecithin cholesterol acyl transferase (LCAT) deficiency is associated with low high-density lipoprotein (HDL) and the presence of an abnormal lipoprotein called lipoprotein X (Lp-X) that contributes to end-stage renal disease. We examined the possibility of using LCAT an as enzyme replacement therapy agent by testing the infusion of human recombinant (r)LCAT into several mouse models of LCAT deficiency. Infusion of plasma from human LCAT transgenic mice into LCAT-knockout (KO) mice rapidly increased HDL-cholesterol (C) and lowered cholesterol in fractions containing very-low-density lipoprotein (VLDL) and Lp-X. rLCAT was produced in a stably transfected human embryonic kidney 293f cell line and purified to homogeneity, with a specific activity of 1850 nmol/mg/h. Infusion of rLCAT intravenously, subcutaneously, or intramuscularly into human apoA-I transgenic mice showed a nearly identical effect in increasing HDL-C approximately 2-fold. When rLCAT was intravenously injected into LCAT-KO mice, it showed a similar effect as plasma from human LCAT transgenic mice in correcting the abnormal lipoprotein profile, but it had a considerably shorter half-life of approximately 1.23 ± 0.63 versus 8.29 ± 1.82 h for the plasma infusion. rLCAT intravenously injected in LCAT-KO mice crossed with human apolipoprotein (apo)A-I transgenic mice had a half-life of 7.39 ± 2.1 h and increased HDL-C more than 8-fold. rLCAT treatment of LCAT-KO mice was found to increase cholesterol efflux to HDL isolated from mice when added to cells transfected with either ATP-binding cassette (ABC) transporter A1 or ABCG1. In summary, rLCAT treatment rapidly restored the normal lipoprotein phenotype in LCAT-KO mice and increased cholesterol efflux, suggesting the possibility of using rLCAT as an enzyme replacement therapy agent for LCAT deficiency.

SUBMITTER: Rousset X

PROVIDER: S-EPMC2957790 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Effect of recombinant human lecithin cholesterol acyltransferase infusion on lipoprotein metabolism in mice.

Rousset Xavier X Vaisman Boris B Auerbach Bruce B Krause Brian R BR Homan Reyn R Stonik John J Csako Gyorgy G Shamburek Robert R Remaley Alan T AT

The Journal of pharmacology and experimental therapeutics 20100706 1

Lecithin cholesterol acyl transferase (LCAT) deficiency is associated with low high-density lipoprotein (HDL) and the presence of an abnormal lipoprotein called lipoprotein X (Lp-X) that contributes to end-stage renal disease. We examined the possibility of using LCAT an as enzyme replacement therapy agent by testing the infusion of human recombinant (r)LCAT into several mouse models of LCAT deficiency. Infusion of plasma from human LCAT transgenic mice into LCAT-knockout (KO) mice rapidly incre ...[more]

PMID: 20605907

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Project description:Background MEDI6012 is recombinant human lecithin cholesterol acyltransferase, the rate-limiting enzyme in reverse cholesterol transport. Infusions of lecithin cholesterol acyltransferase have the potential to enhance reverse cholesterol transport and benefit patients with coronary heart disease. The purpose of this study was to test the safety, pharmacokinetic, and pharmacodynamic profile of MEDI6012. Methods and Results This phase 2a double-blind study randomized 48 subjects with stable coronary heart disease on a statin to a single dose of MEDI6012 or placebo (6:2) (NCT02601560) with ascending doses administered intravenously (24, 80, 240, and 800 mg) and subcutaneously (80 and 600 mg). MEDI6012 demonstrated rates of treatment-emergent adverse events that were similar to those of placebo. Dose-dependent increases in high-density lipoprotein cholesterol were observed with area under the concentration-time curves from 0 to 96 hours of 728, 1640, 3035, and 5318 should be: mg·h/mL in the intravenous dose groups and 422 and 2845 mg·h/mL in the subcutaneous dose groups. Peak mean high-density lipoprotein cholesterol percent change was 31.4%, 71.4%, 125%, and 177.8% in the intravenous dose groups and 18.3% and 111.2% in the subcutaneous dose groups, and was accompanied by increases in endogenous apoA1 (apolipoprotein A1) and non-ATP-binding cassette transporter A1 cholesterol efflux capacity. Decreases in apoB (apolipoprotein B) were observed across all dose levels and decreases in atherogenic small low-density lipoprotein particles by 41%, 88%, and 79% at the 80-, 240-, and 800-mg IV doses, respectively. Conclusions MEDI6012 demonstrated an acceptable safety profile and increased high-density lipoprotein cholesterol, endogenous apoA1, and non-ATP-binding cassette transporter A1 cholesterol efflux capacity while reducing the number of atherogenic low-density lipoprotein particles. These findings are supportive of enhanced reverse cholesterol transport and a functional high-density lipoprotein phenotype. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02601560.

Project description:Lecithin:cholesterol acyltransferase (LCAT) has been shown to play a role in the depletion of lipid oxidation products, but this has so far not been studied in humans. In this study, we investigated processes and parameters relevant to lipid oxidation in carriers of functional LCAT mutations.In 4 carriers of 2 mutant LCAT alleles, 63 heterozygotes, and 63 family controls, we measured activities of LCAT, paraoxonase 1, and platelet-activating factor-acetylhydrolase; levels of lysophosphatidylcholine molecular species, arachidonic and linoleic acids, and their oxidized derivatives; immunodetectable oxidized phospholipids on apolipoprotein (apo) B-containing and apo(a)-containing lipoproteins; IgM and IgG autoantibodies to malondialdehyde-low-density lipoprotein and IgG and IgM apoB-immune complexes; and the antioxidant capacity of high-density lipoprotein (HDL). In individuals with LCAT mutations, plasma LCAT activity, HDL cholesterol, apoA-I, arachidonic acid, and its oxidized derivatives, oxidized phospholipids on apo(a)-containing lipoproteins, HDL-associated platelet-activating factor-acetylhydrolase activity, and the antioxidative capacity of HDL were gene-dose-dependently decreased. Oxidized phospholipids on apoB-containing lipoproteins was increased in heterozygotes (17%; P<0.001) but not in carriers of 2 defective LCAT alleles.Carriers of LCAT mutations present with significant reductions in LCAT activity, HDL cholesterol, apoA-I, platelet-activating factor-acetylhydrolase activity, and antioxidative potential of HDL, but this is not associated with parameters of increased lipid peroxidation; we did not observe significant changes in the oxidation products of arachidonic acid and linoleic acid, immunoreactive oxidized phospholipids on apo(a)-containing lipoproteins, and IgM and IgG autoantibodies against malondialdehyde-low-density lipoprotein. These data indicate that plasma LCAT activity, HDL-associated platelet-activating factor-acetylhydrolase activity, and HDL cholesterol may not influence the levels of plasma lipid oxidation products.

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Effect of recombinant human lecithin cholesterol acyltransferase infusion on lipoprotein metabolism in mice.

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Effect of recombinant human lecithin cholesterol acyltransferase infusion on lipoprotein metabolism in mice.

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