出版社：American Society for Biochemistry and Molecular Biology
摘要：Obese mice without leptin (ob/ob) or the leptin receptor (db/db)have increased plasma HDL levels and accumulate a unique lipoproteinreferred to as LDL/HDL1. To determine the role of apolipoproteinA-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/HDL1particle persisted. The cholesterol in this lipoprotein rangewas associated with both - and ß-migrating particles,confirming the presence of small LDLs and large HDLs. Moreover,in the obese apoA-I–/– mice, LDL particles weresmaller and HDLs were more negatively charged and enriched inapoE compared with controls. This LDL/HDL1 particle was rapidlyremodeled to the size of normal HDL after injection into C57BL/6mice, but it was not catabolized in obese apoA-I–/–mice even though plasma hepatic lipase (HL) activity was increasedsignificantly. The finding of decreased hepatic scavenger receptorclass B type I (SR-BI) protein levels may explain the persistenceof LDL/HDL1 in obese apoA-I–/– mice.
Our studies suggest that the maturation and removal of largeHDLs depends on the integrity of a functional axis of apoA-I,HL, and SR-BI. Moreover, the presence of large HDLs withoutapoA-I provides evidence for an apoA-I-independent pathway ofcholesterol efflux, possibly sustained by apoE.Abbreviations: apoA-I, apolipoprotein A-I; db/db, leptin receptor-deficient; ERR, estrogen-related receptor-; FPLC, fast-protein liquid chromatography; HNF-1, hepatic nuclear factor-1; LDLR, low density lipoprotein receptor; LRP, low density lipoprotein receptor-related protein; ob/ob, leptin-deficient; PPAR, peroxisome proliferator-activated receptor ; 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
- 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
