Brousseau M E, Wang J, Demosky S J, Vaisman B L, Talley G D, Santamarina-Fojo S, Brewer H B, Hoeg J M
Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
J Lipid Res. 1998 Aug;39(8):1558-67.
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.
家族性高胆固醇血症（FH）是一种由低密度脂蛋白受体（LDLr）基因的多种突变引起的疾病，不仅导致低密度脂蛋白胆固醇（LDL-C）浓度升高，还会使高密度脂蛋白（HDL）-C和载脂蛋白（apo）A-I浓度降低。HDL-C和apoA-I的降低是apoA-I分解代谢增加和apoA-I合成减少这两种代谢缺陷共同作用的结果。本研究旨在验证以下假设：在LDLr缺陷的兔子中过表达人卵磷脂胆固醇酰基转移酶（hLCAT）（一种参与HDL代谢的关键酶）会增加HDL-C和apoA-I浓度。建立了两组hLCAT转基因兔子：1）hLCAT+/LDLr杂合子（LDLr+/-）和2）hLCAT+/LDLr纯合子（LDLr-/-）。将hLCAT+兔子的数据与相同LDLr状态的非转基因（hLCAT-）兔子的数据进行比较。在LDLr+/-兔子中，hLCAT+兔子（62±8，59±4）的HDL-C和apoA-I浓度（mg/dl）相对于hLCAT-兔子（21±1，26±2）显著更高。同样，当比较hLCAT+/LDLr-/-（27±2，19±6）和hLCAT-/LDLr-/-（5±1，6±2）兔子时也是如此。动力学实验表明，与hLCAT-（0.588）LDLr+/-兔子相比，hLCAT+（0.376±0.025）兔子中apoA-I的分解代谢率（FCR，d-1）显著延迟，与hLCAT-（1.194±0.138）LDLr-/-兔子相比，hLCAT+（0.666±0.033）兔子中也是如此。在hLCAT+/LDLr+/-（10±2对6）和hLCAT+/LDLr-/-（9±1对4±1）兔子中，apoA-I生成率（PR，mg·kg·d-1）都更高。血浆LCAT活性与HDL-C（r = 0.857）、apoA-I FCR（r = -0.774）和apoA-I PR（r = 0.771）之间存在显著相关性（P < 0.02），而HDL-C与apoA-I FCR（-0.812）和PR（0.751）均相关。总之，这些数据表明，在LDLr缺陷的兔子中过表达hLCAT可通过降低apoA-I分解代谢和增加apoA-I合成来提高HDL-C和apoA-I浓度，从而纠正导致LDLr缺乏时观察到的低α脂蛋白血症的代谢缺陷。
