Disease relevance of GPKOW

• OBJECTIVE: Earlier studies have shown that the fatty acid binding protein 2 (FABP2) T54 allele is associated with dyslipidemia, which in turn correlates with the incidence of cerebrovascular disease (CVD) [1].

High impact information on GPKOW

• To gain insight into the function of human protein kinase X (PrKX), a signal-transduction protein required for macrophage differentiation, we identified regulatory subunit I alpha of protein kinase A, T54 and Smad6 as partners for this protein using a yeast two-hybrid interaction screen [2].
• CDK1 phosphorylates the A-kinase regulatory subunit RIIalpha on threonine 54 (T54) at mitosis, an event proposed to alter the subcellular localization of RIIalpha [3].
• This correlates with T54 phosphorylation of RIIalpha [3].
• DESIGN: Eleven A54 homozygotes and 11 T54 carriers were given 3 oral-fat-tolerance tests (butter, safflower oil, and olive oil) [4].
• CONCLUSIONS: The A54T polymorphism results in a diet-gene interaction: the T54 group had increased chylomicron cholesterol after olive oil only [4].

Biological context of GPKOW

• Obese and diabetic T54 carriers have greater postprandial lipemia than do A54 homozygotes [4].
• An association between genotype and chylomicron cholesterol was seen only after olive oil: values were higher (P = 0.02) in T54 carriers (0.087 +/- 0.006 mmol. h/L) than in A54 homozygotes (0.058 +/- 0.004 mmol. h/L) [4].
• Interestingly, fasting TG concentrations in large TG-rich lipoproteins (large-TRL; S(f) > 400) were correlated with HDL-TG levels at 4 (r = 0.74, p = 0.01) and 8 hours (r = 0.73, p = 0.01) after the test meal in T54/A54 heterozygotes only [5].
• The T54 variant of the FABP2 gene has shown an association with the insulin resistance syndrome in some, but not all, studies [6].

Anatomical context of GPKOW

• Our data are consistent with the T54 IFABP increasing the flux of lipids through the enterocyte leading to an increase in chylomicron secretion [7].
• From this initial sample, 50 men accepted to have their postprandial lipid response assessed and 10 T54/A54 heterozygotes were then individually matched for visceral adipose tissue accumulation and fasting plasma triglyceride (TG) levels with 10 A54/A54 homozygotes [5].

Associations of GPKOW with chemical compounds

• The T54 protein isoform is also associated with increased triacylglycerol secretion in vitro [4].
• OBJECTIVE: We investigated diet-gene interactions by measuring postprandial lipids, glucose, insulin, and C-peptide in healthy, nonobese A54 homozygotes and T54 carriers after ingestion of 3 different fats [4].
• In women, the T54 allele was associated with significantly higher total-cholesterol (5.32+/-1.01 vs. 5.17+/-0.98 mmol/l; P<0.049) and LDL-cholesterol (3.31+/-0.93 vs. 3.18+/-0.85 mmol/l; P<0.023) after adjustment for covariates and menopausal status, estrogen therapy and APOE genotype [7].

Analytical, diagnostic and therapeutic context of GPKOW

• D and V mutations of T54 also reduce affinity for the N-terminal RII-binding domain of AKAP450, whereas small neutral residues do not change affinity detected by surface plasmon resonance [8].

References