Mechanisms of HDL deficiency in mice overexpressing human apoA-II.
To ascertain the mechanisms underlying the hypoalphalipoproteinemia present in mice overexpressing human apolipoprotein A-II (apoA-II) (line 11.1), radiolabeled HDL or apoA-I were injected into mice. Fractional catabolic rate of [(3)H]cholesteryl oleoyl ether HDL ([(3)H]HDL) was 2-fold increased in 11.1 transgenic mice compared with control mice and this was concomitant with increased radioactivity in liver, gonads, and adrenals. However, scavenger receptor class B, type I (SR-BI) was increased only in adrenals. [(3)H]HDL of 11.1 transgenic mice presented greater binding but decreased uptake compared with control mice when Chinese hamster ovary cells transfected with SR-BI were used, thereby pointing to unknown but SR-BI-independent mechanisms as being responsible for the increased (3)H-radioactivity seen in liver and gonads. Synthesis rate (SR) of plasma [(3)H]HDL was 2-fold decreased in 11.1 transgenic mice. Mouse (125)I-apoA-I was 2-fold more rapidly catabolized (mainly by the kidney) in transgenic mice. Mouse apoA-I displacement from HDL by the addition of isolated human apoA-II was reproduced ex vivo; thus, this mechanism may be involved in the increased renal catabolism of apoA-I. ApoA-I SR was 2-fold decreased in 11.1 transgenic mice and this was concomitant with a 2.3-fold decrease in hepatic apoA-I mRNA abundance. Our findings show that multiple mechanisms are involved in the HDL deficiency presented by mice overexpressing human apoA-II.
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D016633:Apolipoprotein A-II / Q000096:biosynthesis* / Q000378:metabolism; D001667:Binding, Competitive; D018955:CD36 Antigens / Q000096:biosynthesis; D016466:CHO Cells / Q000378:metabolism; D008076:Cholesterol, HDL / Q000032:analysis / Q000172:deficiency* / Q000378:metabolism; D006224:Cricetinae; D005260:Female; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D012333:RNA, Messenger / Q000096:biosynthesis; D011869:Radioligand Assay; D014162:Transfection; D014316:Tritium
D000199:Actins; D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D018955:CD36 Antigens; D008076:Cholesterol, HDL; D012333:RNA, Messenger; D014316:Tritium