Abstract 450: Effects of Multiple Infusions of Recombinant LCAT on Plasma and Tissue Lipids and Expression of Genes Involved in Atherogenesis
BACKGROUND LCAT, an enzyme that converts small, discoidal HDL to spherical HDL particles by esterifying free cholesterol, plays a key role in reverse cholesterol transport (RCT). LCAT replacement therapy holds promise for treatment of familial LCAT deficiency, as well as a possible acute treatment in patients with Acute Coronary Syndrome.
HYPOTHESIS Injecting recombinant LCAT into LCAT-deficient mice expressing human apoA-I will increase plasma HDL-C levels, improve reverse cholesterol transport, and alter expression of genes involved in atherosclerosis.
METHODS We injected recombinant human LCAT or vehicle intravenously daily for 4 days into LCAT-KO x human apoA-I transgenic mice (n=4-6 in each group). The dose of rLCAT was approximately 10-fold larger in terms of mass than the endogenous levels of mouse LCAT. Lipids in plasma and tissues, as well as expression of 84 cholesterol metabolism genes in control and experimental groups were measured.
RESULTS Total cholesterol (TC) in plasma increased from 80 (vehicle) to 473 mg/dl (LCAT) (P<0.002) after rLCAT treatment. Cholesteryl esters (CE) increased from 8 (vehicle) to 339 mg/dl (LCAT). Lipids were localized mostly in the HDL fraction. The accumulation of lipids in plasma was accompanied by decreased lipid content in peripheral tissues.TC in aorta, heart, kidney and spleen decreased, by 15%; 27%; 13% and 27%, respectively (P<0.05). In kidney, lung and spleen, CE decreased from 17; 18 and 28 nmol/mg dry weight, respectively, to being below detection. LCAT injections did not significantly alter liver lipid content, but did significantly increase expression of cholesterol synthesis genes (Dhcr7, Hmgcr, Mdv, Mvk and Tm7sf2) and decreased expression of the cholesterol efflux gene Abcg1.To further investigate the potential of interaction between apoA-I and LCAT, we also studied apoA-I-Tg x LCAT-Tg double transgenic mice. Their TC in plasma reached more than 1300 mg/mL, with similar gene expression changes observed in hapoA-I transgenic mice but more pronounced.
CONCLUSIONS The results show the feasibility of using recombinant LCAT as a therapy for LCAT deficiency and for other diseases associated with accumulation of cholesterol in tissues.
- © 2013 by American Heart Association, Inc.