出版社：American Society for Biochemistry and Molecular Biology
摘要：Patients homozygous for Tangier disease have a near absenceof plasma HDL as a result of mutations in ABCA1 and hypercatabolizenormal HDL particles. To determine the relationship betweenABCA1 expression and HDL catabolism, we investigated intravascularremodeling, plasma clearance, and organ-specific uptake of HDLin mice expressing the human apolipoprotein A-I (apoA-I) transgenein the Abca1 knockout background. Small HDL particles (7.5 nm),radiolabeled with 125I-tyramine cellobiose, were injected intorecipient mice to quantify plasma turnover and the organ uptakeof tracer. Small HDL tracer was remodeled to 8.2 nm diameterparticles within 5 min in human apolipoprotein A-I transgenic(hA-ITg) mice (control) and knockout mice. Decay of tracer fromplasma was 1.6-fold more rapid in knockout mice (P < 0.05)and kidney uptake was twice that of controls, with no differencein liver uptake. We also observed 2-fold greater hepatic expressionof ABCA1 protein in hA-ITg mice compared with nontransgenicmice, suggesting that overexpression of human apoA-I stabilizedhepatic ABCA1 protein in vivo.
We conclude that ABCA1 is not required for in vivo remodelingof small HDLs to larger HDL subfractions and that the hypercatabolismof normal HDL particles in knockout mice is attributable toa selective catabolism of HDL apoA-I by the kidney.Abbreviations: apoA-I, apolipoprotein A-I; CE, cholesteryl ester; EC, esterified cholesterol; FC, free cholesterol; FCR, fractional catabolic rate; FPLC, fast-protein liquid chromatography; hA-ITg, human apolipoprotein A-I transgenic; PL, phospholipid; PLTP, phospholipid transfer protein; RCT, reverse cholesterol transport; SR-BI, scavenger receptor class B type I; TC, tyramine cellobiose; WHAM, Wisconsin Hypoalpha Mutant
Supplementary key words apolipoprotein A-I • ATP binding cassette transporter A1 • high density lipoprotein
