Correction of hypoalphalipoproteinemia in LDL receptor-deficient rabbits by lecithin:cholesterol acyltransferase

• Published in: Journal of lipid research Vol. 39; no. 8; pp. 1558 - 1567
• Main Authors: Brousseau, M E, Wang, J, Demosky, Jr, S J, Vaisman, B L, Talley, G D, Santamarina-Fojo, S, Brewer, Jr, H B, Hoeg, J M
• Format: Journal Article
• Language: English
• Published: United States Elsevier 01.08.1998
• Subjects: Animals; Animals, Genetically Modified; apolipoprotein A-I; Apolipoprotein A-I - blood; Base Sequence; Disease Models, Animal; DNA Primers - genetics; familial hypercholesterolemia; Gene Expression; Genetic Therapy; Heterozygote; high density lipoproteins; Homozygote; Humans; Hyperlipoproteinemia Type II - blood; Hyperlipoproteinemia Type II - genetics; Hyperlipoproteinemia Type II - therapy; Hypolipoproteinemias - blood; Hypolipoproteinemias - genetics; Hypolipoproteinemias - therapy; Kinetics; lecithin:cholesterol acyltransferase; Lipids - blood; Lipoproteins - blood; Lipoproteins, HDL - blood; metabolism; Mutation; Phosphatidylcholine-Sterol O-Acyltransferase - blood; Phosphatidylcholine-Sterol O-Acyltransferase - genetics; Rabbits; Receptors, LDL - deficiency; Receptors, LDL - genetics; WHHL rabbit
• ISSN: 0022-2275
• DOI: 10.1016/s0022-2275(20)32184-2

Familial hypercholesterolemia (FH), a disease caused by a variety of mutations in the low density lipoprotein receptor (LDLr) gene, leads not only to elevated LDL-cholesterol (C) concentrations but to reduced high density lipoprotein (HDL)-C and apolipoprotein (apo) A-I concentrations as well. The reductions in HDL-C and apoA-I are the consequence of the combined metabolic defects of increased apoA-I catabolism and decreased apoA-I synthesis. The present studies were designed to test the hypothesis that overexpression of human lecithin:cholesterol acyltransferase (hLCAT), a pivotal enzyme involved in HDL metabolism, in LDLr defective rabbits would increase HDL-C and apoA-I concentrations. Two groups of hLCAT transgenic rabbits were established: 1) hLCAT+/LDLr heterozygotes (LDLr+/-) and 2) hLCAT+/LDLr homozygotes (LDLr-/-). Data for hLCAT+ rabbits were compared to those of nontransgenic (hLCAT-) rabbits of the same LDLr status. In LDLr+/- rabbits, HDL-C and apoA-I concentrations (mg/dl), respectively, were significantly greater in hLCAT+ (62 +/- 8, 59 +/- 4) relative to hLCAT- rabbits (21 +/- 1, 26 +/- 2). This was, likewise, the case when hLCAT+/ LDLr-/- (27 +/- 2, 19 +/- 6) and hLCAT-/LDLr-/- (5 +/- 1, 6 +/- 2) rabbits were compared. Kinetic experiments demonstrated that the fractional catabolic rate (FCR, d(-1)) of apoA-I was substantially delayed in hLCAT+ (0.376 +/- 0.025) versus hLCAT- (0.588) LDLr+/- rabbits, as well as in hLCAT+ (0.666 +/- 0.033) versus hLCAT- (1.194 +/- 0.138) LDLr-/- rabbits. ApoA-I production rate (PR, mg x kg x d(-1)) was greater in both hLCAT+/LDLr+/- (10 +/- 2 vs. 6) and hLCAT+/LDLr-/- (9 +/- 1 vs. 4 +/- 1) rabbits. Significant correlations (P < 0.02) were observed between plasma LCAT activity and HDL-C (r = 0.857), apoA-I FCR (r = -0.774), and apoA-I PR (r = 0.771), while HDL-C correlated with both apoA-I FCR (-0.812) and PR (0.751). In summary, these data indicate that hLCAT overexpression in LDLr defective rabbits increases HDL-C and apoA-I concentrations by both decreasing apoA-I catabolism and increasing apoA-I synthesis, thus correcting the metabolic defects responsible for the hypoalphalipoproteinemia observed in LDLr deficiency.