Persistence of high density lipoprotein particles in obese mice lacking apolipoprotein A-I.
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.
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Marnie L
ML
Gruen
Michelle R
MR
Plummer
Wenwu
W
Zhang
Kelly A
KA
Posey
MacRae F
MF
Linton
Sergio
S
Fazio
Alyssa H
AH
Hasty
D000818:Animals; D016632:Apolipoprotein A-I / Q000172:deficiency* / Q000502:physiology; D018955:CD36 Antigens; D003433:Crosses, Genetic; D015870:Gene Expression; D008049:Lipase / Q000097:blood; D008074:Lipoproteins / Q000096:biosynthesis / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood*; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000097:blood* / Q000235:genetics*; D010316:Particle Size; D012333:RNA, Messenger / Q000032:analysis; D011971:Receptors, Immunologic / Q000032:analysis / Q000235:genetics; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B
D016632:Apolipoprotein A-I; D018955:CD36 Antigens; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; C035392:high density lipoprotein-1; D008049:Lipase; C495700:Lipc protein, mouse