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标题：Correction of hypoalphalipoproteinemia in LDL receptor-deficient rabbits by lecithin:cholesterol acyltransferase
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作者：Margaret E. Brousseau ; Jian Wang ; Stephen J. Demosky 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：1998
卷号：39
期号：8
页码：1558-1567
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：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·kg·d^–1) was greater in both hLCAT+/LDLr+/– (10 ± 2 vs. 6) and hLCAT+/LDLr–/– (9 ± 1 vs. 4 ± 1) rabbits. Significant correlations ( P 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.—Brousseau, M. E., J. Wang, S. J. Demosky, Jr., B. L. Vaisman, G. D. Talley, S. Santamarina-Fojo, H. B. Brewer, Jr., and J. M. Hoeg. Correction of hypoalphalipoproteinemia in LDL receptor-deficient rabbits by lecithin:cholesterol acyltransferase. J. Lipid. Res. 39: 1558–1567.
关键词：familial hypercholesterolemia ; high density lipoproteins ; apolipoprotein A-I ; metabolism ; lecithin:cholesterol acyltransferase ; WHHL rabbit