Persistence of high density lipoprotein particles in obese mice lacking apolipoprotein A-I
Persistence of high density lipoprotein particles in obese mice lacking apolipoprotein A-I
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DOI：
10.1194/jlr.m500181-jlr200
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发表时间：
2005-09-01
影响因子：
6.5
通讯作者：
Hasty, AH
中科院分区：
文献类型：
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作者：
Gruen, ML;Plummer, MR;Hasty, AH
没有瘦素（ob/ob）或瘦素受体（db/db）的肥胖小鼠血浆HDL水平升高，并积累了称为LDL/HDL 1的独特脂蛋白。为了确定载脂蛋白A-I（apoA-I）在LDL/HDL 1形成和蓄积中的作用，将ob/ob和db/db小鼠与apoA-I缺陷（apoA-I-/-）背景杂交。尽管肥胖的apoA-I-/-小鼠的HDL水平预期会显著降低，但LDL/HDL 1颗粒仍然存在。该脂蛋白范围内的胆固醇与α和β迁移颗粒相关，证实了小LDL和大HDL的存在。此外，与对照组相比，肥胖apoA-I-/-小鼠的LDL颗粒更小，HDL带更多负电荷，富含apoE。这种LDL/HDL 1颗粒注射到C57 BL/6 6小鼠后迅速重塑为正常HDL的大小，但在肥胖apoA-I-/-小鼠中，即使血浆肝脂酶（HL）活性显著增加，它也没有被分解代谢。肝脏清道夫受体B I型（SR-BI）蛋白水平降低的发现可能解释了肥胖apoA-I-/-小鼠中LDL/HDL 1的持续存在。我们的研究表明，大HDL的成熟和去除取决于apoA-I，HL和SR-BI功能轴的完整性。此外，没有载脂蛋白A-I的大HDL的存在提供了一个apoA-I-独立的胆固醇流出途径，可能由apoE维持的证据。
Obese mice without leptin (ob/ob) or the leptinreceptor (db/db) have increased plasma HDL levels and accumulate a unique lipoprotein referred to as LDL/HDL1. To determine the role of apolipoprotein A-I (apoA-I) in the formation and accumulation of LDL/HDL1, both ob/ob and db/db mice were crossed onto an apoA-I-deficient (apoA-I-/-) background. Even though the obese apoA-I-/- mice had an expected dramatic decrease in HDL levels, the LDL/HDL1 particle persisted. The cholesterol in this lipoprotein range was associated with both alpha- and beta-migrating particles, confirming the presence of small LDLs and large HDLs. Moreover, in the obese apoA-I-/- mice, LDL particles were smaller and HDLs were more negatively charged and enriched in apoE compared with controls. This LDL/HDL1 particle was rapidly remodeled to the size of normal HDL after injection into C57BL/6 6 mice, but it was not catabolized in obese apoA-I-/- mice even though plasma hepatic lipase (HL) activity was increased significantly. The finding of decreased hepatic scavenger receptor class B type I (SR- BI) protein levels may explain the persistence of LDL/HDL1 in obese apoA-I-/- mice. Our studies suggest that the maturation and removal of large HDLs depends on the integrity of a functional axis of apoA-I, HL, and SR-BI. Moreover, the presence of large HDLs without apoA-I provides evidence for an apoA-I-independent pathway of cholesterol efflux, possibly sustained by apoE.