Ng D S, Francone O L, Forte T M, Zhang J, Haghpassand M, Rubin E M
Human Genome Center, Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720, USA.
J Biol Chem. 1997 Jun 20;272(25):15777-81. doi: 10.1074/jbc.272.25.15777.
Lecithin:cholesterol acyltransferase (LCAT) is the major determinant of the cholesteryl ester (CE) content of high density lipoprotein (HDL) in plasma. The selective uptake of HDL-CE is postulated to participate in delivery of tissue-derived cholesterol both to the liver and steroidogenic tissues. Recent studies comparing mice with similarly low levels of HDL, due to the absence of either of the two major HDL-associated apolipoproteins apoA-I and apoA-II, suggest that apoA-I is crucial in modulating this process, possibly through interaction with scavenger receptor class B type I (SR-BI). Because of the central role of LCAT in determining the size, lipid composition, and plasma concentration of HDL, we have created LCAT-deficient mice by gene targeting to examine the effect of LCAT deficiency on HDL structure and composition and adrenal cholesterol delivery. The HDL in the LCAT-deficient mice was reduced in its plasma concentration (92%) and CE content (96%). The HDL particles were heterogeneous in size and morphology and included numerous discoidal particles, mimicking those observed in LCAT-deficient humans. The adrenals of the male Lcat (-/-) mice were severely depleted of lipid stores, which was associated with a 2-fold up-regulation of the adrenal SR-BI mRNA. These studies demonstrate that LCAT deficiency, similar to apoA-I deficiency, is associated with a marked decrease in adrenal cholesterol delivery and supports the hypothesis that adrenal SR-BI expression is regulated by the adrenal cholesterol.
卵磷脂胆固醇酰基转移酶（LCAT）是血浆中高密度脂蛋白（HDL）胆固醇酯（CE）含量的主要决定因素。HDL-CE的选择性摄取被认为参与了将组织来源的胆固醇输送到肝脏和类固醇生成组织的过程。最近的研究比较了由于缺乏两种主要的HDL相关载脂蛋白载脂蛋白A-I和载脂蛋白A-II而导致HDL水平同样较低的小鼠，结果表明载脂蛋白A-I在调节这一过程中至关重要，可能是通过与B类I型清道夫受体（SR-BI）相互作用来实现的。由于LCAT在决定HDL的大小、脂质组成和血浆浓度方面起着核心作用，我们通过基因靶向技术创建了LCAT缺陷小鼠，以研究LCAT缺陷对HDL结构和组成以及肾上腺胆固醇输送的影响。LCAT缺陷小鼠的HDL血浆浓度降低了92%，CE含量降低了96%。HDL颗粒在大小和形态上是异质性的，包括许多盘状颗粒，类似于在LCAT缺陷的人类中观察到的颗粒。雄性Lcat（-/-）小鼠的肾上腺脂质储存严重耗尽，这与肾上腺SR-BI mRNA上调2倍有关。这些研究表明，与载脂蛋白A-I缺乏相似，LCAT缺乏与肾上腺胆固醇输送的显著减少有关，并支持肾上腺SR-BI表达受肾上腺胆固醇调节的假说。
