Disease relevance of APOA5

• Following treatment with the LXR ligand T0901317, we found that APOA5 mRNA levels were decreased in hepatoma cell lines [1].
• These findings suggest the possible use of c.553G>T polymorphisms in APOA5 as prognostic indicators for hypertriglyceridemia susceptibility in Chinese [2].
• These results suggest a potential contribution of the APOA5 gene in hypertriglyceridemia associated with hyperinsulinemia [3].
• Another recent clue to the molecular pathogenesis of familial combined hyperlipidemia is the association of the high triglyceride trait with the APOA5 gene, located on 11q [4].
• APOA5 gene variants, lipoprotein particle distribution, and progression of coronary heart disease: results from the LOCAT study [5].

Psychiatry related information on APOA5

• This study investigates the association of AD with the APOA5 gene -1131T>C polymorphisms in samples of 106 patients with Alzheimer's disease (AD), 76 elderly healthy controls and 93 young healthy controls [6].

High impact information on APOA5

• In humans, single nucleotide polymorphisms (SNPs) across the APOAV locus were found to be significantly associated with plasma triglyceride levels in two independent studies [7].
• These findings indicate that APOAV is an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease [7].
• Mice expressing a human APOAV transgene showed a decrease in plasma triglyceride concentrations to one-third of those in control mice; conversely, knockout mice lacking Apoav had four times as much plasma triglycerides as controls [7].
• In this issue of the JCI, Marçais et al. report that the rare Q139X mutation in APOA5 leads to severe hypertriglyceridemia by exerting a dominant-negative effect on the plasma lipolytic system for triglyceride-rich lipoproteins [8].
• Severe hypertriglyceridemia in 8 heterozygotes was strictly associated with the presence on the second allele of 1 of 2 previously described triglyceride-raising minor APOA5 haplotypes [9].

Chemical compound and disease context of APOA5

• Recent findings indicate that APOA5 could also influence cholesterol homeostasis and probably play a role in hypertriglyceridemia associated with diabetes and inflammation [10].
• The absence of significant changes in Apoa5 gene expression during chronic fructose-induced TG elevation excludes its major role in mechanisms compensating severe hypertriglyceridemia [11].

Biological context of APOA5

• Single nucleotide polymorphisms (SNPs) in APOA5 (S19W, -1131T>C) and APOA4 (T347S, Q360H) and an APOA4/A5 intergenic T>C SNP were examined in a large study of healthy middle-aged men (n=2808) [12].
• APOA5 19WW and -1131CC men had 52% and 40% higher TG (P<0.003) compared to common allele homozygotes, respectively, effects which were independent and additive [12].
• Thus variation in APOA5 is associated with differences in TGs in healthy men, independent of those previously reported for APOC3, while association between APOA4 and TG reflects linkage disequilibrium with these sites [12].
• Taken together, our results demonstrate that APOA5 gene expression is regulated by the LXR ligand T0901317 in a negative manner through SREBP-1c [1].
• Finally, administration of T0901317 to hAPOA5 transgenic mice revealed a significant decrease of APOA5 mRNA in liver tissue and circulating apolipoprotein AV protein in plasma, confirming that the described down-regulation also occurs in vivo [1].

Anatomical context of APOA5

• Rosiglitazone had no effect on Apoa5 mRNA in cultured rat hepatocytes [13].
• No intact PPAR (peroxisome proliferator-activated receptor) response element was identified in the rat Apoa5 promoter [13].
• We studied the effects of APOA5 polymorphisms on plasma triglyceride levels in Turks, a population with low levels of HDL cholesterol and a high prevalence of coronary artery disease [14].
• The identification of APOA5 as a T3 target gene provides a new potential mechanism whereby thyroid hormones can influence triglyceride homeostasis [15].
• APOA5 polymorphisms influence plasma triglycerides in young, healthy African Americans and whites of the CARDIA Study [16].

Associations of APOA5 with chemical compounds

• In this study, we investigated the contribution of APOA5 to the liver X receptor (LXR) ligand-mediated effect on plasma triglyceride levels [1].
• Dietary information was obtained from the Institute of Agricultural Economy. Results: In APOA5 Ser19Ser homozygotes (n=105), plasma cholesterol was relatively stable over the years (6.1+/-1.3 and 5.6+/-1.0 mmol/L in 1988 and 1996), but the decrease was much higher in Trp19 carriers (n=27; 6.5+/-1.6 vs. 5.1+/-1.1 mmol/L) [17].
• Both rosiglitazone and the fish oil diet significantly increased Apoa5 mRNA, by about 70%, but tended to lower liver and plasma apoAV [13].
• OBJECTIVE: Both the apolipoprotein A5 and C3 genes have repeatedly been shown to play an important role in determining plasma triglyceride concentrations in humans and mice [18].
• SUBJECTS, MATERIALS AND METHODS: Plasma APOA5 concentration was measured by ELISA in 215 subjects with type 2 diabetes, who were taken from the Diabetes Atorvastatin Lipid-lowering Intervention (DALI) study, a 30-week randomised, double-blind, placebo-controlled study, and given atorvastatin 10 mg or 80 mg daily [19].

Physical interactions of APOA5

• Using an oligonucleotide precipitation assay for USF from nuclear extracts, we demonstrate that phosphorylated USF1 fails to bind to the APOA5 promoter [3].
• The presented data support the idea that the molecular mechanism of APOA5 function may include the enhancement of binding between lipoproteins and proteoglycans at the vascular wall and activation of proteoglycan-bound lipoprotein lipase [8].

Regulatory relationships of APOA5

• The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element [20].

Other interactions of APOA5

• The major TG-raising alleles were defined by APOA5 W19 and APOC3 -482T [12].
• 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 [21].
• Of the individual SNPs tested in the case-control panel, the strongest evidence of association was obtained with SNPs in APOA1 (P=0.001) and APOA5 (P=0.001) [22].
• Treatment with atorvastatin decreased plasma APOA5, APOC3, APOE and triglycerides [19].
• METHODS AND RESULTS: We sequenced APOA5 gene in 10 hypertriglyceridemic patients in whom mutations in LPL and APOC2 genes had been excluded [23].

Analytical, diagnostic and therapeutic context of APOA5

• Electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated that this APOA5 E box binds upstream stimulatory factors (USFs) [3].
• After treatment, APOC3 remained the major determinant of plasma triglyceride levels (59%), while the contributions of APOA5 and APOE were insignificant (2 and 3%) [19].
• The aim of this study was to investigate the influence of APOA5 variants on fasting lipids and to the response to both an oral fat tolerance test (OFTT) and an oral glucose tolerance test (OGTT) [24].
• Triglyceride plays a role in coronary artery disease (CAD), so this case-control study tested for a possible link between these two APOA5 polymorphisms, their common haplotypes and the risk of CAD [25].
• Furthermore, ultracentrifugation fraction analysis indicated in carriers an altered association of Apoa5 truncated and WT proteins to lipoproteins, whereas in normal plasma, Apoa5 associated with VLDL and HDL/LDL fractions [9].

References