Disease relevance of APOA4

• The APOA4 T347S variant is associated with reduced plasma TAOS in subjects with diabetes mellitus and cardiovascular disease [1].
• Response of apolipoprotein AIV and lipoproteins to glycaemic control in young people with insulin-dependent diabetes mellitus [2].
• Apolipoprotein AIV gene variant S347 is associated with increased risk of coronary heart disease and lower plasma apolipoprotein AIV levels [3].
• A method to screen apolipoprotein polymorphisms in whole plasma: description of apolipoprotein A-IV variants in dyslipidemias and a reassessment of apolipoprotein A-I in Tangier disease [4].
• Logistic regression analysis confirmed that the presence of the APOA4 His360 allele predicts an increased risk of progression of coronary atherosclerosis in adults with type 1 diabetes of long duration (odds ratio = 3.3, p=0.003 after adjustment for covariates associated with CAD risk) [5].

Psychiatry related information on APOA4

• Serum apolipoprotein A-IV levels changed significantly from baseline in response to each dietary modification [6].
• Association of the apolipoprotein A-IV codon 360 mutation in patients with Alzheimer's disease [7].
• Intestinal expression of human apolipoprotein A-IV in transgenic mice fails to influence dietary lipid absorption or feeding behavior [8].

High impact information on APOA4

• Protection against atherogenesis in mice mediated by human apolipoprotein A-IV [9].
• ApoA-IV plays a potentially important role in lipoprotein metabolism and reverse cholesterol transport, but its in vivo metabolism is poorly understood [10].
• Intestinal mRNA abundance of 2 candidate genes involved in lipid transport, mtp and apob, was unchanged, although serum levels of apolipoprotein A-IV were reduced [11].
• The synthesis rates and messenger RNA levels of two other chylomicron apoproteins (apolipoprotein A-I and apolipoprotein A-IV) were found to be reduced by 50% [12].
• The distinctive biological properties of apolipoprotein A-IV suggest that its concentration in serum should be specifically regulated by dietary triglyceride [6].

Chemical compound and disease context of APOA4

• The accumulation of apolipoprotein A-IV in high density lipoproteins from patients with end-stage renal disease might reflect the impaired reversed cholesterol transport mechanisms which are believed to be a major cause of the high prevalence of atherosclerotic diseases in these patients [13].

Biological context of APOA4

• However, the associations could also have resulted from linkage disequilibrium with other functional variants in APOC3 or the closely linked APOA1 and/or APOA4 genes [14].
• Estimation of the extent of nonrandom association between these polymorphisms indicated considerable linkage disequilibrium within the APOA1-APOC3-APOA4 gene cluster [15].
• DNA polymorphism haplotypes of the human apolipoprotein APOA1-APOC3-APOA4 gene cluster [15].
• The genes coding for apolipoprotein A1 (APOA1), apolipoprotein C3 (APOC3) and apolipoprotein A4 (APOA4) are tandemly organised within a short region on chromosome 11q23-q24 [16].
• However, there is no evidence that APOA5 S19W, -12,238T > C, APOA4 T347S and APCC3 -482C > T SNPs are major risk factors of CHD in French men [17].

Anatomical context of APOA4

• Finally, restriction mapping analysis of DNA from a patient with combined APOA1-APOC3 deficiency and premature coronary artery disease indicated that this patient has a structurally normal APOA4 gene [18].
• The effect of apolipoprotein A-IV on hepatic lipase-catalyzed dolichol acylation and phospholipid hydrolysis was studied in model membranes and compared with the effects of apolipoprotein A-I and E. Apolipoprotein A-IV strongly stimulated dolichol acylation and phosphatidylethanolamine hydrolysis but partly inhibited phosphatidylcholine hydrolysis [19].
• The effect of peptide YY, a gastrointestinal hormone, on the expression of the apolipoprotein A-IV gene in the intestinal epithelial cell line Caco-2 was examined by semiquantitative RT-PCR followed by Southern hybridization with an inner oligonucleotide probe [20].
• Identification of a detergent-solubilized plasma membrane protein from rat liver recognizing apolipoprotein A-IV [21].
• Using isoelectric focusing and immunoblotting, we have analyzed plasmas from 188 non-insulin-dependent diabetic and 238 normoglycemic Hispanic individuals from the San Luis Valley, Colorado, to determine APOA4 genotype frequencies and to estimate the impact of the genotypes on quantitative traits [22].

Associations of APOA4 with chemical compounds

• The APOC3/-455 and APOA4 T347S variants showed significant effects on HDL cholesterol in girls (P = 0.033 and P = 0.016, respectively) [23].
• These results demonstrate that genetic variation in and around APOA4, independent of the effects of triglyceride, is associated with risk of CHD and apoAIV levels, supporting an antiatherogenic role for apoAIV [3].
• Apolipoprotein A-IV strongly stimulated the hydrolysis of phosphatidylcholine and phosphatidylethanolamine in both lipoproteins, while the hydrolysis of triglycerides was completely inhibited [19].
• The surface binding constants followed the same order as the respective solution binding constants: Ka (ATIII) greater than Ka (Apo-AIV) greater than Ka (C3) greater than Ka (Apo-AI), indicating that protein binding to the immobilized heparin used is not essentially different from solution binding [24].
• Apolipoprotein A-IV, apolipoprotein E-2 and apolipoprotein E-3 were individually incorporated into defined phosphatidylcholine/cholesterol liposomes for study of lecithin:cholesterol acyltransferase activation [25].

Physical interactions of APOA4

• Human apolipoprotein A-IV binds to apolipoprotein A-I/A-II receptor sites and promotes cholesterol efflux from adipose cells [26].

Regulatory relationships of APOA4

• Apolipoprotein A-I had only a minor influence on the various activities studied and could not replace apolipoprotein A-IV [19].
• Peptide YY stimulates the expression of apolipoprotein A-IV gene in Caco-2 intestinal cells [20].
• ApoA-IV proteoliposomes also activated LA-PLTP in a concentration-dependent manner, whereas apoA-I proteoliposomes had no such effect [27].
• E-cadherin-dependent transcriptional control of apolipoprotein A-IV gene expression in intestinal epithelial cells: a role for the hepatic nuclear factor 4 [28].

Other interactions of APOA4

• An intron interrupting the 5' noncoding region of the APOA1 and APOC3 mRNAs is absent from the corresponding position of the APOA4 mRNA [18].
• The effect of apolipoprotein A-IV on hepatic lipase activity was then studied with the gum arabic-stabilized triglyceride emulsion [19].
• Apolipoprotein A-I, apolipoprotein E, and apolipoprotein A-IV in triglyceride-rich lipoproteins (containing chylomicrons, VLDL, and remnants) exhibit more complex kinetics [29].
• The present results suggest that peptide YY modulates apolipoprotein A-IV gene expression, likely via the Y1-receptor subtype in intestinal epithelial cells [20].
• Apolipoprotein A-IV (apoA-IV) might play an important role in lipoprotein metabolism, including modulation of triglyceride-rich lipoprotein catabolism, reverse cholesterol transport and cholesteryl ester transfer protein (CETP) activity [30].

Analytical, diagnostic and therapeutic context of APOA4

• The association of two APOA5 SNPs [S19W (SNP5), -1131T>C (SNP3)] and an APOA4/A5 intergenic SNP [-12238T>C (SNP4)] were examined in healthy young men (n=774) who had undergone both an OFTT and an OGTT [31].
• Western blotting revealed that the exogenous peptide YY increased the intracellular concentration of apolipoprotein A-IV [20].
• Identical apolipoprotein A-IV isoprotein patterns were observed when either antibodies to lymph or plasma apolipoprotein A-IV were used for immunoblotting [4].
• Apolipoprotein A-IV (apo A-IV) is present in plasma associated to both HDL and as a complex with lipids that cannot be floated by ultracentrifugation at 1.21 g/ml density [21].
• Serum apolipoprotein A-IV and lipoprotein cholesterol in patients undergoing total parenteral nutrition [32].

References