Effects of fenofibrate on apolipoprotein kinetics in patients with coexisting dysbetalipoproteinemia and heterozygous familial hypercholesterolemia

Dysbetalipoproteinemia (dysb) and familial hypercholesterolemia (FH) are two genetic disorders giving rise to severe disturbances of lipid homeostasis and premature atherosclerosis. The co-occurrence of both metabolic abnormalities is very rare and is estimated to affect I individual per 2,500,000 in the general population. However, the relative contribution of these two dyslipidemias to the combined lipoprotein phenotype is unknown. The two objectives of this study were (1) to compare the in vivo kinetics of triglyceride-rich lipoprotein (TRL) apolipoprotein (apo) 1348, VLDL, IDL and LDL apo B 100 as well as plasma apo A-l labelled with a stable isotope (L-(5,5,5-D-3) leucine) in two subjects presenting both heterozygous FH and dysbetalipoproteinemia (FH+/dysb+), in six FH heterozygotes and in five normolipidemic controls, and (2) to examine the impact of a 6-week treatment with micronized fenofibrate 200 mg/d on apolipoprotein kinetics in FH+/dysb+. As compared with FH heterozygotes and controls, the two FH+/dysb+ subjects showed elevated TRL apo B48 and VLDL, IDL apo 13100 pool sizes (PS) mainly due to lower fractional catabolic rates (FCR). Moreover, as compared with FH heterozygotes, FH+/dysb+ subjects presented lower LDL apo B 100 PS due to a higher FCR. Pool size, FCR and production rate (PR) of apo A-l were higher in FH+/dysb+ subjects than in FH heterozygotes. In FH+/dysb+ subjects, fenofibrate treatment was associated with a decreased TRL apo B48 PS (-52 and -61%), VLDL apo 13100 (-61 and -63%) and IDL apo 13100 (-37 and -16%) and an increased FCR of TRL apo B48 (10 and 67%), VLDL apo 13100 (123 and 57%) and IDL apo 13100 (29 and 10%). Fenofibrate also increased LDL apo 13100 PS (3 and 57%) due to an increase in PR (80 and 26%) but had divergent effects on LDL apo 13100 FCR. These results indicate that the coexistence of dysbetalipoproteinemia and heterozygous FH results in a mixed lipoprotein phenotype that is intermediate between the two pure phenotypes and that fenofibrate treatment partially reverses lipoprotein abnormalities, mostly through changes in PR and FCR of apo B48- and B100-containing lipoproteins. (c) 2005 Elsevier Ireland Ltd. All rights reserved.