A Thr⁹⁴Ala mutation in human liver fatty acid-binding protein contributes to reduced hepatic glycogenolysis and blunted elevation of plasma glucose levels in lipid-exposed subjects

Abstract

Liver fatty acid-binding protein (L-FABP) is a highly conserved key factor in lipid metabolism. Amino acid replacements in L-FABP might alter its function and thereby affect glucose metabolism in lipid-exposed subjects, as indicated by studies in L-FABP knockout mice. Amino acid replacements in L-FABP were investigated in a cohort of 1,453 Caucasian subjects. Endogenous glucose production (EGP), gluconeogenesis, and glycogenolysis were measured in healthy carriers of the only common Thr(94)-to-Ala amino acid replacement (Ala/Ala(94)) vs. age-, sex-, and BMI-matched wild-type (Thr/Thr(94)) controls at baseline and after 320-min lipid/heparin-somatostatin-insulin-glucagon clamps (n = 18). Whole body glucose disposal was further investigated (subset; n = 13) using euglycemic-hyperinsulinemic clamps without and with lipid/heparin infusion. In the entire cohort, the only common Ala/Ala(94) mutation was significantly associated with reduced body weight, which is in agreement with a previous report. In lipid-exposed, individually matched subjects there was a genotype vs. lipid-treatment interaction for EGP (P = 0.009) driven mainly by reduced glycogenolysis in Ala/Ala(94) carriers (0.46 +/- 0.05 vs. 0.59 +/- 0.05 mgxkg(-1)xmin(-1), P = 0.013). The lipid-induced elevation of plasma glucose levels was smaller in Ala/Ala(94) carriers compared with wild types (P < 0.0001). Whole body glucose disposal was not different between lipid-exposed L-FABP genotypes. In summary, the Ala/Ala(94)-mutation contributed significantly to reduced glycogenolysis and less severe hyperglycemia in lipid-exposed humans and was further associated with reduced body weight in a large cohort. Data clearly show that investigation of L-FABP phenotypes in the basal overnight-fasted state yielded incomplete information, and a challenge test was essential to detect phenotypical differences in glucose metabolism between L-FABP genotypes.

Implications from a pharmacogenomic analysis:Nerium oleanderleaf distillate supplemented diet regulates cholesterol metabolism in rats

“…HFD rats express the gene 11.5-fold lower than the ND rats, interestingly NOHFD caused DOI: 10.3109/13880209.2013.874535 four-fold up-regulation in the gene expression level, closer to the normal value. Fabp1 gene encodes fatty acid-binding protein which plays a significant role in fatty acid uptake, transport and metabolism (Chen et al, 1986;Weickert et al, 2007). Fatty acid-binding protein activity is tightly regulated by peroxisome proliferator-activated-receptor (Ppar) signaling pathway ( Figure 5).…”

Impact of L-FABP and glucose on polyunsaturated fatty acid induction of PPARα-regulated β-oxidative enzymes

“…11,21,60,82,99,124,128). The phenotype of L-FABP-null mice exhibits significant similarities to that of humans carrying the L-FABP T94A variant (3): 1) ablation of L-FABP reduced VLCn-3 PUFA and LCFA uptake (5,69,70,118), a phenotype shared by "Chang liver" cells overexpressing human L-FABP T94A variant vs. WT L-FABP overexpressors (23); 2) serum triglyceride was increased in L-FABP-null mice (3,4,61,64,65,77), a phenotype shared by humans with the L-FABP T94A variant (10, 21); 3) synthetic (fibrate) and natural (branchedchain LCFA) peroxisome proliferators were less effective in lowering serum and hepatic triglycerides in L-FABP-null mice (6,7).…”

“…Thus PUFAs may be more effective in inducing transcription of PPAR␣-regulated genes, especially in the fatty acid ␤-oxidation pathway, in the context of high glucose. The potential role of L-FABP in lowering serum triglyceride levels is underscored by studies in humans reporting a L-FABP T94A polymorphism that occurs with high frequency, 32-37% of (10 -13% homozygous) in all populations studied to date (11,21,99,124,128). The T94A substitution raises serum LDL cholesterol and triglyceride, traits associated with increased risk of cardiovascular disease and Type 2 diabetes (10, 21), and decreases LCFA uptake in cultured cells (23).…”

Loss of intracellular lipid binding proteins differentially impacts saturated fatty acid uptake and nuclear targeting in mouse hepatocytes

“…Therapeutic interest in L-FABP has increasingly focused on L-FABP's protection against hepatocellular oxidative stress, as in diabetes (56,76,77,85), and on developing fibrate analogs better bound and targeted by L-FABP for activating PPAR␣ (13,62,82). Part of this interest is based on the discovery of the L-FABP T94A variant, which is the most frequently occurring polymorphism in the entire FABP protein family, with a 26 -38% minor allele frequency (8.3 ϩ 1.9% frequency of homozygous variant) in multiple populations tested worldwide [mutation annotation format for 1,000 genomes in National Center for Biotechnology Information singlenucleotide polymorphism database; ALFRED database] (11,18,38,54,61,80,84). The human L-FABP T94A variant is Values are means Ϯ SE (n ϭ 3).…”