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 Ϯ 0.63 versus 8.29 Ϯ 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 Ϯ 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.

Nephrotic Syndrome Caused by Immune-Mediated Acquired LCAT Deficiency

“…19 FLD could be an attractive candidate for enzyme replacement therapy, because LCAT acts in the plasma compartment, without any organspecific distribution. 20 In mouse models of LCAT deficiency, human recombinant LCAT treatment rapidly restored the normal lipoprotein phenotype in LCAT-knockout mice, and increased the cholesterol efflux. 20 Enzyme replacement therapy for human congenital LCAT efficiency is still under development.…”

“…20 In mouse models of LCAT deficiency, human recombinant LCAT treatment rapidly restored the normal lipoprotein phenotype in LCAT-knockout mice, and increased the cholesterol efflux. 20 Enzyme replacement therapy for human congenital LCAT efficiency is still under development. 21 Our case report provides encouraging evidence to suggest that restoration of LCAT activity in patients with LCAT deficiency could induce resolution of the abnormal lipid deposition.…”

Lecithin:cholesterol acyltransferase: old friend or foe in atherosclerosis?

“…The plasma concentration of LCAT is about 6 g/ml and varies little in adult humans with age, gender, and smoking ( 36 ). The half-life of human LCAT in plasma has been estimated to be 4-5 days ( 37 ) LCAT reversibly binds to lipoproteins and is primarily found on HDL, which likely prevents its rapid clearance from the circulation ( 38 ). ApoAI is the most potent activator of LCAT, which enables it to convert free cholesterol into cholesteryl esters on HDL by a transesterifi cation reaction involving the transfer of a fatty acid by guest, on May 10, 2018 www.jlr.org…”

Cellular Pregnenolone Esterification by Acyl-CoA:Cholesterol Acyltransferase

“…WT and Lcat1 Ϫ/Ϫ mice maintained at NIH were also congenic C57BL6 as described previously (17). Mice were fed ad libitum with standard chow diet, maintained in a pathogen-free environment and kept on a 12-h light/dark schedule.…”