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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:2188.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

ATP-Binding Cassette Transporter G8 Gene As a Determinant of Apolipoprotein B-100 Kinetics in Overweight Men

D.C. Chan; G.F. Watts; P.H.R. Barrett; A.J. Whitfield; F.M. van Bockxmeer

From the Lipoprotein Research Unit (D.C.C., G.F.W., P.H.R.B.), School of Medicine and Pharmacology, The Western Australian Institute for Medical Research; and School of Surgery and Pathology (A.J.W., F.M.vB.), University of Western Australia and Department of Biochemistry, Royal Perth Hospital, Perth, Australia.

Correspondence to Professor Gerald F. Watts, School of Medicine and Pharmacology, University of Western Australia, GPO Box X2213, Perth, Western Australia 6847. E-mail gfwatts{at}cyllene.uwa.edu.au

Objective— We examined the influence of genetic variation of the ATP-binding cassette (ABC) transporter G8 on apolipoprotein B (apoB) kinetics in overweight/obese men.

Methods and Results— Very low–density lipoprotein (VLDL) and low-density lipoprotein (LDL) apoB kinetics were determined in 47 men (body mass index 32±3 kg/m²) using stable isotope and multicompartmental modeling to estimate production rate (PR), fractional catabolic rate (FCR), and VLDL to LDL–apoB conversion. Relative to the wild-type (400TT), subjects carrying the ABCG8 400K allele had significantly decreased plasma concentrations of triglycerides, sitosterol, and campesterol, lower PR of VLDL–apoB, and higher VLDL to LDL–apoB conversion (P<0.05). The PR and FCR of LDL–apoB were also significantly higher with 400K allele (P<0.05). No association was found with ABCG8 D19H. Compared with APOE2 or APOE3, APOE4 carriers had significantly higher plasma LDL-cholesterol concentrations and lower LDL–apoB FCR. During multiple regression analysis including age, homeostasis model assessment score, plasma concentrations of sitosterol, and lathosterol, ABCG8 and apoE genotypes were independent determinants of VLDL–apoB PR and LDL–apoB FCR, respectively (P<0.05).

Conclusions— Variation in the ABC transporter G8 appears to independently influence the metabolism of apoB-containing lipoproteins in overweight/obese subjects. This may have therapeutic implications for the management of dyslipidemia in these subjects.

This study demonstrates that subjects carrying the ABCG8 400K allele had lower production rate of VLDL–apoB and higher VLDL to LDL–apoB conversion. The production rate and fractional catabolic rate of LDL–apoB were also higher with 400K allele. During multiple regression analysis, ABCG8 genotype was an independent determinant of VLDL–apoB production rate.

Key Words: ATP binding cassette transporter • lipoprotein metabolism • obesity • cardiovascular disease

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