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Originally published In Press as doi:10.1194/jlr.M500181-JLR200 on July 1, 2005

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Journal of Lipid Research, Vol. 46, 2007-2014, September 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

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

Marnie L. Gruen*, Michelle R. Plummer*, Wenwu Zhang{dagger}, Kelly A. Posey*, MacRae Linton{dagger},§, Sergio Fazio{dagger},** and Alyssa H. Hasty1,*

* Departments of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232
{dagger} Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
§ Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232
** Pathology, Vanderbilt University Medical Center, Nashville, TN 37232

Published, JLR Papers in Press, July 1, 2005. DOI 10.1194/jlr.M500181-JLR200

1 To whom correspondence should be addressed. e-mail: 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 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 ß-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.

Abbreviations: apoA-I, apolipoprotein A-I; db/db, leptin receptor-deficient; ERR{alpha}, estrogen-related receptor-{alpha}; FPLC, fast-protein liquid chromatography; HNF-1{alpha}, hepatic nuclear factor-1{alpha}; LDLR, low density lipoprotein receptor; LRP, low density lipoprotein receptor-related protein; ob/ob, leptin-deficient; PPAR{alpha}, peroxisome proliferator-activated receptor {alpha}; SR-BI, scavenger receptor class B type I; TC, total cholesterol; TG, triglyceride

Supplementary key words small, dense low density lipoproteins • remodeling • obesity • scavenger receptor class B type I • hepatic lipase


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