Mechanisms of HDL deficiency in mice overexpressing human apoA-II

• Published in: Journal of lipid research 2002-10, Vol.43 (10), p.1734-1742
• Main Authors: Julve, Josep, Escolà-Gil, Joan Carles, Ribas, Vicent, González-Sastre, Francesc, Ordóñez-Llanos, Jordi, Sánchez-Quesada, José Luis, Blanco-Vaca, Francisco
• Format: Article
• Language: English
• Subjects: Actins - biosynthesis; Animals; apoA-I; apoA-II transgenic mice; Apolipoprotein A-I - metabolism; Apolipoprotein A-II - biosynthesis; Apolipoprotein A-II - metabolism; Binding, Competitive; CD36 Antigens - biosynthesis; CHO Cells - metabolism; Cholesterol, HDL - analysis; Cholesterol, HDL - deficiency; Cholesterol, HDL - metabolism; Cricetinae; Female; Humans; hypoalphalipoproteinemia; Kinetics; lipoprotein metabolism; Liver - metabolism; Mice; Mice, Transgenic; Organ Specificity; Radioligand Assay; RNA, Messenger - biosynthesis; Transfection; Tritium
• ISSN: 0022-2275
• DOI: 10.1194/jlr.M200081-JLR200

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.