Persistence of high density lipoprotein particles in obese mice lacking apolipoprotein AI

Marnie L. Gruen, Michelle R. Plummer, Wenwu Zhang, Kelly A. Posey, MacRae F. Linton, Sergio Fazio, and Alyssa H. Hasty

Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232-0615

Corresponding Author: alyssa.hasty{at}vanderbilt.edu

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 apoAI in the formation and accumulation of LDL/HDL1, both ob/ob and db/db mice were crossed onto an apolipoprotein AI deficient (apoAI^-/-) background. Even though the obese apoAI^-/- mice had an expected dramatic fall 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 LDL and large HDL. Moreover, in the obese apoAI^-/- mice LDL particles were smaller and HDL were more negatively charged and enriched in apoE compared to controls. This LDL/HDL1 particle was rapidly remodeled to the size of normal HDL after injection into C57BL/6 mice, but was not catabolized in obese apoAI^-/- mice even though plasma hepatic lipase (HL) activity was significantly increased. The finding of decreased hepatic SR-BI protein levels may explain the persistence of LDL/HDL1 in obese apoAI^-/- mice. Our studies suggest that the maturation and removal of large HDL depends on the integrity of a functional axis of apoAI, HL and SR-BI. Moreover, the presence of large HDL without apoAI provides evidence for an apoAI-independent pathway of cholesterol efflux, possibly sustained by apoE.

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