Effect of liver fatty acid binding protein (FABP) T94A missense mutation on plasma lipoprotein responsiveness to treatment with fenofibrate
Effect of liver fatty acid binding protein (FABP) T94A missense mutation on plasma lipoprotein responsiveness to treatment with fenofibrate
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DOI：
10.1007/s10038-004-0171-2
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发表时间：
2004-01-01
影响因子：
3.5
通讯作者：
Vohl, MC
中科院分区：
文献类型：
--
作者：
Brouillette, C;Bossé, Y;Vohl, MC
非诺贝特是一种过氧化物酶体增殖激活受体α（PPARalpha）激动剂，已被证明可降低血浆甘油三酯（TG）和升高血浆高密度脂蛋白（HDL）胆固醇水平，尽管个体间反应差异很大。非诺贝特激活的PPARalpha与靶基因调控区中存在的称为PPARresponseelement（PPRE）的DNA序列元件结合。已在编码肝脂肪酸结合蛋白（LFABP）的基因的近端5'侧翼区鉴定出PPRE。LFABP是存在于肝脏和肠中的14 kDa的小胞质蛋白，并且是脂肪酸结合蛋白（FABPs）超家族的成员。FABP在长链脂肪酸（LCFA）及其CoA-酯溶解到各种细胞内细胞器中发挥作用。FABPs作为LCFA的细胞内受体，并且它们也可能在将LCFA运输到细胞核中的PPARs的配体依赖性反式激活中具有影响。由于已知PPARs调节参与脂质代谢的许多基因的转录，因此必须考虑LFABP在脂肪酸摄取中的重要性。本研究的目的是验证LFABP基因的遗传变异是否可能影响空腹状态下的血浆脂蛋白/脂质水平，以及对非诺贝特降脂治疗对血浆脂质和肥胖变量的反应。我们还想验证PPARalpha L162 V突变的存在是否与LFABP基因中的遗传变异相互作用。为了实现这一目标，我们首先确定了人类LFABP基因的基因组结构，然后设计了内含子引物序列的编码区，所有外显子-内含子剪接边界，和基因的启动子区在24例患者表现出不同的血浆脂蛋白/脂质反应非诺贝特。序列分析显示，在外显子3存在T94 A错义突变。种间比较表明，苏氨酸94是保守的物种之间。随后，我们筛选了另一个样本的130例法裔加拿大受试者与非诺贝特治疗的LFABP T94 A突变的存在。非诺贝特治疗后，A94等位基因携带者血浆TG水平高于2.00 mmol/l的风险增加[2.75（1.03-7.34）; OR 95%置信区间（CI）]。此外，A94等位基因携带者的特征是基线血浆游离脂肪酸水平（FFA）较高（p=0.01），体重指数（BMI）较低（p=0.05）和腰围（p=0.005）比T94纯合子。此外，PPARalpha L162 V和LFABP T94 A显示出对BMI具有协同作用（p相互作用=0.03）。这些结果表明，LFABP T94 A错义突变可能影响肥胖指数以及非诺贝特降脂治疗后出现残留高血脂症的风险。
Fenofibrate, a peroxisome proliferated activated receptor alpha (PPARalpha) agonist, has been shown to decrease plasma triglyceride (TG) and increase plasma high-density lipoprotein (HDL) cholesterol levels despite a large interindividual variation in the response. Fenofibrate-activated PPARalpha binds to a DNA sequence element termed PPAR response element (PPRE) present in regulatory regions of target genes. A PPRE has been identified in the proximal 5' flanking region of the gene encoding the liver fatty acid binding protein (LFABP). LFABP is a small cytosolic protein of 14 kDa present in the liver and the intestine and is a member of the superfamily of the fatty acid binding proteins (FABPs). FABPs play a role in the solubilization of long-chain fatty acids (LCFAs) and their CoA-ester to various intracellular organelles. FABPs serves as intracellular acceptors of LCFAs, and they may also have an impact in ligand-dependent transactivation of PPARs in trafficking LCFAs to the nucleus. Since PPARs are known to regulate the transcription of many genes involved in lipid metabolism, the importance of LFABP in fatty acid uptake has to be considered. The aim of this study was to verify whether genetic variations in the LFABP gene may impact on plasma lipoprotein/lipid levels in the fasting state as well as on the response to a lipid-lowering therapy with fenofibrate on plasma lipids and obesity variables. We also wanted to verify whether the presence of the PPARalpha L162V mutation interacts with genetic variants in LFABP gene. To achieve this goal, we first determined the genomic structure of the human LFABP gene and then designed intronic primers to sequence the coding regions, all exon-intron splicing boundaries, and the promoter region of the gene in 24 patients showing divergent plasma lipoprotein/lipid response to fenofibrate. Sequence analysis revealed the presence of a T94A missense mutation in exon 3. Interspecies comparison revealed that threonine 94 is conserved among species. We subsequently screened another sample of 130 French Canadian subjects treated with fenofibrate for the presence of the LFABP T94A mutation. Carriers of the A94 allele were at increased risk to exhibit plasma TG levels above 2.00 mmol/l after treatment with fenofibrate [2.75 (1.03-7.34); OR 95% confidence interval (CI)]. In addition, carriers of the A94 allele were characterized by higher baseline plasma-free fatty acid levels (FFA) (p=0.01) and by a lower body mass index (BMI) (p=0.05) and waist circumference (p=0.005) than T94 homozygotes. Moreover, PPARalpha L162V and LFABP T94A showed to have a synergistic effect on BMI (p interaction=0.03). These results suggest that the LFABP T94A missense mutation could influence obesity indices as well as the risk to exhibit residual hypertriglyceridmia following a lipid-lowering therapy with fenofibrate.