ABCA1: In addition to increased HDL-C, overexpression of ABCA1 in C57Bl mice (ABCA1-Tg) fed an athero diet, decreased plasma cholesterol, apoB-containing lipoproteins (B-Lp) and apoB. Compared to controls, ABCA1-Tg mice had decreased plasma levels of total cholesterol, non-HDL-C, and apoB and increased plasma levels of HDL-C and apoA-I. FPLC confirmed a decrease in nonHDL-C and increased HDL-C in ABCA1-Tg compared to controls. This unanticipated beneficial effect of ABCA1 overexpression on the pro-atherogenic B-Lp significantly contributes to the marked decrease in diet-induced aortic atherosclerosis in ABCA1-Tg mice. To identify the mechanisms by which ABCA1 increased HDL-C and decreased the B-Lp, we performed kinetic studies in ABCA1-Tg and C57Bl mice for 15 wks on the pro-atherogenic diet. Compared to controls, the fractional catabolic rates (FCR) for ABCA1-Tg injected with 3H-CEt HDL and 125I-ApoA-l HDL decreased while the apoA-l production rates were similar. Thus, the increased plasma HDL levels in ABCA1-Tg is due to delayed catabolism of apoA-I. In contrast, 131l-apoB-Lp kinetics demonstrated markedly enhanced catabolism of B-Lps in ABCA1-Tg compared to control mice and similar PR. Direct quantitation of apoB production rates by the 35S-methionine/triton method confirmed similar apoB production rates. Western blot analysis revealed a 2-fold increase in hepatic LDLr expression. Thus, the decreased B-Lp in ABCA1-Tg is due to enhanced LDLr-mediated B-Lp catabolism. In summary: 1) ABCA1 increased HDL-C by decreasing HDL catabolism and decreasing B-Lp by increased B-Lp catabolism; 2) The LDLr plays an important role in facilitating ABCA1-induced decrease in B-Lps; 3) ABCA1 modulates not only HDL but also B-Lp metabolism resulting in a protective lipoprotein profile that decreases diet-induced atherosclerosis in C57Bl/6.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Intramural Research (Z01)
Project #
1Z01HL002010-31
Application #
6683976
Study Section
(MDB)
Project Start
Project End
Budget Start
Budget End
Support Year
31
Fiscal Year
2002
Total Cost
Indirect Cost
Name
U.S. National Heart Lung and Blood Inst
Department
Type
DUNS #
City
State
Country
United States
Zip Code