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

J Lipid Res. 2005 Sep;46(9):2007-14. doi: 10.1194/jlr.M500181-JLR200. Epub 2005 Jul 1.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apolipoprotein A-I / deficiency*
  • Apolipoprotein A-I / physiology
  • CD36 Antigens
  • Crosses, Genetic
  • Gene Expression
  • Lipase / blood
  • Lipoproteins / biosynthesis
  • Lipoproteins / blood
  • Lipoproteins, HDL / blood*
  • Lipoproteins, LDL / blood
  • Liver / chemistry
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / blood*
  • Obesity / genetics*
  • Particle Size
  • RNA, Messenger / analysis
  • Receptors, Immunologic / analysis
  • Receptors, Immunologic / genetics
  • Receptors, Scavenger
  • Scavenger Receptors, Class B

Substances

  • Apolipoprotein A-I
  • CD36 Antigens
  • Lipoproteins
  • Lipoproteins, HDL
  • Lipoproteins, LDL
  • RNA, Messenger
  • Receptors, Immunologic
  • Receptors, Scavenger
  • Scavenger Receptors, Class B
  • high density lipoprotein-1
  • Lipase
  • Lipc protein, mouse