Effect of liver fatty acid binding protein (FABP) T94A missense mutation on plasma lipoprotein responsiveness to treatment with fenofibrate

Abstract

Fenofibrate, a peroxisome proliferated activated receptor alpha (PPARa) agonist, has been shown to decrease plasma triglyceride (TG) and increase plasma highdensity lipoprotein (HDL) cholesterol levels despite a large interindividual variation in the response. Fenofibrate-activated PPARa 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 PPARa 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, PPARa 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.

Recent insights into the biological functions of liver fatty acid binding protein 1

“…A common human FABP1 genetic variation at sequence position 94, a threonine to alanine amino acid replacement (T94A), has been identifi ed ( 97 ). Carriers of this SNP have higher baseline plasma free fatty acid levels, lower body mass index, and a smaller waist circumference than T94/T94 homozygotes.…”

L-FABP directly interacts with PPARα in cultured primary hepatocytes

“…For example, human variants in the L-FABP gene exhibit elevated fasting LDL-cholesterol and triglyceride levels-traits associated with increased risk of CVD, type 2 diabetes, and metabolic syndrome ( 35,36 ). This phenotype was exacerbated by treatment with fenofi brate ( 36 ).…”

“…For example, human variants in the L-FABP gene exhibit elevated fasting LDL-cholesterol and triglyceride levels-traits associated with increased risk of CVD, type 2 diabetes, and metabolic syndrome ( 35,36 ). This phenotype was exacerbated by treatment with fenofi brate ( 36 ). The genetic mutations PPAR ␣ L162V and L-FABP T94A together show a synergistic effect on the basal metabolic index in humans, suggesting that the L-FABP T94A missense mutation might infl uence obesity indices and increase the risk of residual hypertriglyceridemia following a lipid lowering therapy with fenofi brate ( 36 ).…”

“…This phenotype was exacerbated by treatment with fenofi brate ( 36 ). The genetic mutations PPAR ␣ L162V and L-FABP T94A together show a synergistic effect on the basal metabolic index in humans, suggesting that the L-FABP T94A missense mutation might infl uence obesity indices and increase the risk of residual hypertriglyceridemia following a lipid lowering therapy with fenofi brate ( 36 ). Finally, increased L-FABP expression is associated with insulin-dependent diabetes and gestational diabetes in humans, streptozotocin-induced diabetes or obesity in rats, and type 1 diabetes in mice (37)(38)(39)(40).…”

Loss of liver FA binding protein significantly alters hepatocyte plasma membrane microdomains

“…L-FABP upregulation in SCP-2-/SCP-x-null mice decreased hepatic cholesterol concomitant with biliary hypersecretion of cholesterol ( 34 ). In Caucasians, a T94A polymorphism occurs in L-FABP with a frequency of 32-37% (10-13% homozygous) (35)(36)(37) and is associated with elevated serum LDL cholesterol and triglycerides, traits associated with increased risk of cardiovascular disease and diabetes mellitus ( 36,38 ). Transfected human Chang liver hepatoma cells overexpressing the L-FABP T94A substitution exhibited cholesterol accumulation ( 39 ).…”