Effects of estrogenic oral contraceptives on the lipoprotein B

Apolipoproteins E and C-III are modulators of lipoprotein metabolism that could affect development of atherosclerosis. The prevalence in plasma of apoB-containing particles (LpB) that contain either apoE or apoC-III, both or neither, and the effect of estrogen on these lipoproteins are unknown. The LpB particle system, defined by the presence or absence of apoE or C-III, was studied in 13 normolipidemic women, 7 nonusers and 6 users of oral contraceptives. Fasting plasma was separated by anti-apoE and CIII affinity chromatography and ultracentrifugation into four types of VLDL, IDL, and LDL particles: with apoE but not apoC-III (E 1 C 2 ), apoC-III but not apoE (E 2 C 1 ), both (E 1 C 1 ) or neither (E 2 C 2 ). The predominant VLDL particles were E 2 C 2 (42% in nonusers, 56% in users) and E 1 C 1 (39% in nonusers, 24% in users), suggesting that apoE and apoC-III mainly exist together in VLDL. In IDL, E 2 C 2 was the major fraction (74% nonusers, 81% users), and in LDL, it was 99% in both groups. The triglycerides in VLDL and IDL were mainly contained in C 1 particles (79% and 66% of the total VLDL and IDL triglycerides, respectively). Within VLDL, IDL, and LDL, E 2 C 2 particles had the smallest size and E 1 C 1 or E 2 C 1 the largest. Users had higher concentrations of VLDL E 2 C 2 (280%) and IDL E 2 C 2 (90%) particles than nonusers. They also had higher free cholesterol and cholesteryl ester concentrations associated with these fractions and with VLDL E 2 C 1 . The triglyceride contents of VLDL E 2 C 2 particles were lower in users of oral contraceptives than in nonusers. This study demonstrates that the elevated VLDL TG concentrations in users of estrogen-dominant oral contraceptives is mainly caused by an increased concentration of small VLDL particles that have reduced TG content, and that do not have apoE and C-III. These particles may have lower atherogenicity than particles enriched with apoE and C-III.— Khoo, C., H. Campos, H. Judge, and F. M. Sacks. Effects of estrogenic oral contraceptives on the lipoprotein B particle system defined by apolipoproteins E and C-III content. J. Lipid Res. 1999. 40: 202–212. Supplementary key words apoB • apoE • apoC-III • estrogen • oral contraceptives • atherosclerosis • lipoproteins • triglyceride • cholesterol Very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) particles are heterogeneous in size and content of triglyceride, cholesterol, and in particular, of specific apolipoproteins. Two major apolipoproteins that are contained in VLDL and IDL, apoC-III and E, play antagonistic roles in the metabolism of VLDL and IDL. ApoC-III inhibits lipoprotein lipase and opposes the apoE-mediated hepatic uptake by cells in culture (1, 2). Transgenic mice, which overexpress the human apoC-III gene, develop hypertriglyceridemia and have a greatly reduced clearance rate of the apoC-III-enriched VLDL particles (3, 4). Hypertriglyceridemic patients have higher synthetic rates of apoC-III and higher concentrations of apoC-III-enriched VLDL (5). Persons deficient in apoC-III and A-I have rapid conversion of VLDL to IDL and low density lipoprotein (LDL) and reduced VLDL triglyceride concentration (6). Responsibility of the apoC-III rather than the apoA-I or high density lipoprotein (HDL) for the low triglycerides in those patients is suggested by the hypotriglyceridemia produced in mice by deleting the apoCIII gene (7). In contrast, apoE acts as a ligand for the LDL receptor and LDL receptor-related protein to mediate clearance of the VLDL, IDL, and LDL particles (8–10). ApoE deficiency in humans and in mice with gene deletion severely impairs VLDL clearance (11–13) and produces hyperlipidemia (11). The plasma concentration of apoC-III has been implicated as a risk factor for coronary heart disease (14, 15). The ratio of apoC-III in (VLDL 1 LDL)/HDL correlated with worsening coronary atherosclerosis, suggesting that apoC-III-containing VLDL is atherogenic in humans (16, Abbreviations: TG, triglyceride; apo, apolipoprotein; VLDL, very low density lipoprotein; LDL, low density lipoprotein; IDL, intermediate density lipoprotein; HDL, high density lipoprotein; hyperTG, hypertriglyceridemia; OC, oral contraceptives; CHD, coronary heart disease; CVD, cardiovascular disease; NaSCN, sodium thiocyanate; LpB, apoB-containing lipoprotein. 1 To whom correspondence should be addressed. by gest, on D ecem er 5, 2016 w w w .j.org D ow nladed fom