Tremblay André J, Lamarche Benoît, Ruel Isabelle L, Hogue Jean-Charles, Deshaies Yves, Gagné Claude, Couture Patrick
Lipid Research Center, CHUL Research Center, Que., Canada.
Atherosclerosis. 2006 Sep;188(1):203-12. doi: 10.1016/j.atherosclerosis.2005.10.037. Epub 2005 Dec 6.
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 1 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) B48, VLDL, IDL and LDL apo B100 as well as plasma apo A-l labelled with a stable isotope (l-(5,5,5-D3) 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 B100 pool sizes (PS) mainly due to lower fractional catabolic rates (FCR). Moreover, as compared with FH heterozygotes, FH+/dysb+ subjects presented lower LDL apo B100 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 B100 (-61 and -63%) and IDL apo B100 (-37 and -16%) and an increased FCR of TRL apo B48 (10 and 67%), VLDL apo B100 (123 and 57%) and IDL apo B100 (29 and 10%). Fenofibrate also increased LDL apo B100 PS (3 and 57%) due to an increase in PR (80 and 26%) but had divergent effects on LDL apo B100 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.
异常β脂蛋白血症（dysb）和家族性高胆固醇血症（FH）是两种导致脂质稳态严重紊乱和早发性动脉粥样硬化的遗传疾病。这两种代谢异常同时出现的情况非常罕见，据估计在普通人群中每250万人中会有1人受影响。然而，这两种血脂异常对合并脂蛋白表型的相对贡献尚不清楚。本研究的两个目的是：（1）比较在两名同时患有杂合子FH和异常β脂蛋白血症（FH+/dysb+）的受试者、六名FH杂合子和五名血脂正常对照者中，富含甘油三酯脂蛋白（TRL）载脂蛋白（apo）B48、极低密度脂蛋白（VLDL）、中间密度脂蛋白（IDL）和低密度脂蛋白（LDL）apo B100以及用稳定同位素（l-(5,5,5-D3)亮氨酸）标记的血浆apo A-1的体内动力学；（2）研究每天服用200毫克微粒化非诺贝特进行6周治疗对FH+/dysb+受试者载脂蛋白动力学的影响。与FH杂合子和对照者相比，两名FH+/dysb+受试者的TRL apo B48和VLDL、IDL apo B100池大小（PS）升高，主要是由于分数分解代谢率（FCR）较低。此外，与FH杂合子相比，FH+/dysb+受试者的LDL apo B100 PS较低，原因是FCR较高。FH+/dysb+受试者的apo A-1池大小、FCR和生成率（PR）高于FH杂合子。在FH+/dysb+受试者中，非诺贝特治疗与TRL apo B48 PS降低（-52%和-61%）、VLDL apo B100（-61%和-63%）和IDL apo B100（-37%和-16%）相关，以及TRL apo B48（10%和67%）、VLDL apo B100（123%和57%）和IDL apo B100（29%和10%）的FCR增加。非诺贝特还因PR增加（80%和26%）而使LDL apo B100 PS增加（3%和57%），但对LDL apo B100 FCR有不同影响。这些结果表明，异常β脂蛋白血症和杂合子FH共存导致了一种混合脂蛋白表型，该表型介于两种纯合表型之间，并且非诺贝特治疗部分逆转了脂蛋白异常，主要是通过改变含apo B48和B100的脂蛋白的PR和FCR实现的。
