Lecithin Cholesterol Acyltransferase (LCAT) deficiency is a rare autosomal recessive disorder due to mutations in the LCAT gene. It associated with a marked reduction in HDL and the presence of an abnormal lipoprotein particle called LpX, which gets traps in the glomerulus and can lead to end stage renal disease in the third or fourth decade of life. LCAT is a relatively stable serum enzyme with a half-life of approximately 3 days humans. It catalyzes the esterification of cholesterol, which raises HDL and promotes the efflux of excess cellular cholesterol and is, therefore, thought to be anti-atherogenic. We examined the possibility of treating LCAT deficiency by enzyme replacement therapy. Recombinant LCAT purified from transfected 293 cells was found to raise HDL-C 7-fold in LCAT K/O mice 4h after a single intravenous bolus injection. Furthermore, LpX levels became undetectable after 4 h and the LCAT treatment normalized the rest of the lipoprotein profile of these mice, which persisted for at least 48 h. In vitro LCAT treatment of serum from patients with LCAT deficiency showed similar changes. Cholesterol on the abnormal LpX particle was esterified, which resulted in the transformation of the abnormal particle into a LDL-like particle and the generation of HDL-like particles by the transfer of phospholipid, cholesteryl ester, and apoA-I from Lpx to the HDL-like particles. In squirrel monkeys, human LCAT delivered by adenovirus was also shown to significantly raise HDL-C, while at the same time lowering LDL-C. Future studies will be aimed at examining the effect of recombinant LCAT on renal disease in mice with LCAT deficiency. In addition, long term treatment with recombinant LCAT will be used in LCAT x apoE double K/O mice for testing this potential therapy on atherosclerosis.
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