TY - JOUR
T1 - Persistence of high density lipoprotein particles in obese mice lacking apolipoprotein A-I
AU - Gruen, Marnie L.
AU - Plummer, Michelle R.
AU - Zhang, Wenwu
AU - Posey, Kelly A.
AU - Linton, MacRae F.
AU - Fazio, Sergio
AU - Hasty, Alyssa H.
PY - 2005/9
Y1 - 2005/9
N2 - 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 α- and β-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.
AB - 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 α- and β-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.
KW - Hepatic lipase
KW - Obesity
KW - Remodeling
KW - Scavenger receptor class B type I
KW - Small, dense low density lipoproteins
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U2 - 10.1194/jlr.M500181-JLR200
DO - 10.1194/jlr.M500181-JLR200
M3 - Article
C2 - 15995171
AN - SCOPUS:24344483109
SN - 0022-2275
VL - 46
SP - 2007
EP - 2014
JO - Journal of lipid research
JF - Journal of lipid research
IS - 9
ER -