Persistence of high density lipoprotein particles in obese mice lacking apolipoprotein A-I.

Gruen ML, Plummer MR, Zhang W, Posey KA, Linton MF, Fazio S, Hasty AH
J Lipid Res. 2005 46 (9): 2007-14

PMID: 15995171 · DOI:10.1194/jlr.M500181-JLR200

Obese mice without leptin (ob/ob) or the leptin receptor (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 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.

MeSH Terms (19)

Animals Apolipoprotein A-I CD36 Antigens Crosses, Genetic Gene Expression Lipase Lipoproteins Lipoproteins, HDL Lipoproteins, LDL Liver Mice Mice, Inbred C57BL Mice, Knockout Obesity Particle Size Receptors, Immunologic Receptors, Scavenger RNA, Messenger Scavenger Receptors, Class B

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