Disease relevance of APOA1

• The ratios of HDL/total cholesterol and APOA1/APOB were also lower in presence of parental myocardial infarction (p less than .001 and p less than .01, respectively) [1].
• The APOA1/C3/A4 locus may account for approximately 8% of the difference between baseline and total possible risk of NIDDM in overweight individuals [2].
• Human data raised the possibility that coronary heart disease is associated with mutations in the apolipoprotein gene cluster APOA1/C3/A4 that result in multideficiency of cluster-encoded apolipoproteins and hypoalphalipoproteinemia [3].
• Interestingly, logistic regression analysis showed that subjects with elevated serum levels of leptin, insulin, TG, APOA1, and reduced level of serum HDL-C displayed increased risk of developing breast cancer than those with the normal levels, respectively [4].
• CRF patients with vascular disease tended to have higher serum concentrations of triglycerides, cholesterol and ApoB and lower ApoA-I/ApoC-III and ApoA-I/ApoB ratios than patients without vascular disease [5].

Psychiatry related information on APOA1

• RESULTS: For serum retinol--after adjustment for sex, age, body mass index, alcohol consumption, oral contraceptive use, and serum albumin, triacylglycerol, and apolipoprotein A-I concentrations--additive genetic effects and shared common environment contributed 30.5% and 14.2% of the total variance, respectively [6].
• Apolipoprotein E alleles but neither apolipoprotein B nor apolipoprotein AI/CIII alleles are associated with late onset, familial Alzheimer's disease [7].
• The effects of dietary modification of phospholipid acyl chains on cellular cholesterol efflux were directly examined by isolating the HDL phospholipid and combining it with human apolipoprotein A-I to form well-defined reconstituted HDL particles [8].
• The volitional factors appeared to influence HDL cholesterol indirectly: Obesity and physical activity were affected primarily through their associations with triglycerides, and alcohol use and smoking through associations with apolipoprotein A-I [9].
• Plasma levels of total cholesterol, HDL-C, LDL-C, triglycerides, apolipoprotein A-I, and apolipoprotein B were measured and correlated with Aggression Questionnaire ratings in 20 young adult males with personality disorders and/or a high propensity toward aggressive behavior and in 40 control subjects [10].

High impact information on APOA1

• Levels of apolipoprotein A-I and apolipoprotein A-II were also associated with decreased risk [11].
• In cerebrospinal fluid from untreated patients with cerebrotendinous xanthomatosis, immunoreactive apolipoprotein B or apolipoprotein B fragment was increased about 100-fold and albumin about 3.5-fold; apolipoprotein AI, apolipoprotein D, and lecithin:cholesterol acyltransferase were 1.5 to 3 times more concentrated [12].
• These findings indicate that the polymorphism in the region between the apolipoprotein A-I and apolipoprotein C-III genes may be a useful marker for the risk of premature coronary artery disease and familial hypoalphalipoproteinemia [13].
• Apolipoprotein A-I gene polymorphism associated with premature coronary artery disease and familial hypoalphalipoproteinemia [13].
• Therefore, we assessed the association between levels of apolipoprotein B, apolipoprotein A-I, lipids, and lipoprotein cholesterols in children and the reported histories of myocardial infarction in their parents in a survey of 2416 black and white school-age children [14].

Chemical compound and disease context of APOA1

• The elevated serum levels of leptin, insulin, TG, APOA1, and reduced level of serum HDL-C may be correlated with increased risk of breast cancer, suggesting that one way of preventing breast cancer would be carried out by controlling the intake of food [4].
• Substitutions of glutamate 110 and 111 in the middle helix 4 of human apolipoprotein A-I (apoA-I) by alanine affect the structure and in vitro functions of apoA-I and induce severe hypertriglyceridemia in apoA-I-deficient mice [15].
• ApoA-I-induced signaling was abrogated by glyburide, an inhibitor of the ABC transporter family, and in fibroblasts from patients with Tangier disease, which do not express ABCA1 [16].
• CONCLUSION: In postmenopausal Greek women with breast cancer, the levels of Lp(a) and triglycerides and the ApoAI/ApoB ratio respond more favorably to tamoxifen treatment in ApoE4-negative than in ApoE4-positive patients [17].
• Apolipoprotein A-I concentration was influenced more notably by estrogen use, total cholesterol and apolipoprotein E; levels of triglycerides, apolipoprotein B, BMI, age and alcohol consumption are less important [18].

Biological context of APOA1

• Allele frequencies for each RFLP were in agreement with previous studies in Caucasian populations for the APOA1/SstI marker [19].
• Extended haplotypes and linkage disequilibrium between 11 markers at the APOA1-C3-A4 gene cluster on chromosome 11 [19].
• The genes coding for apolipoproteins (apo) AI, CIII, and AIV, designated APOA1, APOC3, and APOA4, respectively, are closely linked and tandemly organized in the long arm of the human chromosome 11 [20].
• In contrast to APOA1 and APOC3 genes, which contain three introns, the APOA4 gene contains only two [21].
• To explore this paradigm, we studied a baboon apolipoprotein gene cluster (APOA1/C3/A4/A5) for which the human gene orthologs have well-established roles in influencing plasma HDL-cholesterol and triglyceride concentrations [22].

Anatomical context of APOA1

• 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 [21].
• Apolipoprotein A-I-stimulated apolipoprotein E secretion from human macrophages is independent of cholesterol efflux [23].
• Apolipoprotein A-I (apoA-I)-mediated cholesterol efflux involves the binding of apoA-I to the plasma membrane via its C terminus and requires cellular ATP-binding cassette transporter (ABCA1) activity [23].
• ApoA-I also stimulates secretion of apolipoprotein E (apoE) from macrophage foam cells, although the mechanism of this process is not understood [23].
• 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 [24].

Associations of APOA1 with chemical compounds

• On the other hand, apoprotein A1 (APOA1) and triglyceride levels were not different between the two groups [1].
• The genes coding for three proteins of the plasma lipid transport system--apolipoproteins A1 (APOA1), C3 (APOC3), and A4 (APOA4)--are closely linked and tandemly organized on the long arm of human chromosome 11 [21].
• Variation in the apolipoprotein A1 gene (APOA1) might influence the function of the protein, and thus brain cholesterol metabolism, leading to an increased risk for AD [25].
• The variant, ApoA1 Baltimore, was due to a mutation at codon 34 of the third exon of the APOA1 gene (CGA to CTA) that resulted in an arginine-to-leucine substitution at the tenth amino acid of the mature ApoA1 and a change in charge of -1 [26].
• Gene-drug interaction: additive influence of mutant APOA1 and testosterone on plasma HDL-cholesterol [27].

Physical interactions of APOA1

• To elucidate further the conformation of human apolipoprotein A-I (apoA-I) in lipid-bound states and its effect on the reaction with lecithin cholesterol acyltransferase (LCAT), we prepared reconstituted HDL (rHDL) particles from a reaction mixture containing dipalmitoylphosphatidylcholine/cholesterol/apoA-I in the molar ratios of 150:7.5:1 [28].
• Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits A beta aggregation and toxicity [29].
• The ApoA-I structure was analyzed to detect the site bound by Hpt [30].
• In support of this, the stimulatory role of apolipoprotein A-I was less prominent for DMPC-bound PON1 than for DMPS-bound PON1 [31].
• Fibrocystic disease, type of hormone binding, and recurrence within 3 years were significantly related to apolipoprotein changes, especially apolipoprotein D levels with hormone receptor binding and the apolipoprotein A-I/apolipoprotein B ratio with breast cancer recurrence [32].

Enzymatic interactions of APOA1

• Apolipoprotein A-I activates protein kinase C alpha signaling to phosphorylate and stabilize ATP binding cassette transporter A1 for the high density lipoprotein assembly [33].
• We conclude that, upon HDL oxidation with peroxynitrite, apolipoprotein AI increases the formation of phosphatidylcholine core aldehydes that are subsequently hydrolyzed by PON1 [34].

Regulatory relationships of APOA1

• Apolipoprotein A-I promotes the formation of phosphatidylcholine core aldehydes that are hydrolyzed by paraoxonase (PON-1) during high density lipoprotein oxidation with a peroxynitrite donor [34].
• Apolipoprotein A-I had only a minor influence on the various activities studied and could not replace apolipoprotein A-IV [24].
• Tyrosine modification is not required for myeloperoxidase-induced loss of apolipoprotein A-I functional activities [35].
• Apolipoprotein A-I obtained by the cold ethanol method activated lecithin-cholesterol acyltransferase to the same extent as apolipoprotein A-I prepared by the classical flotation method [36].
• Apolipoprotein A-I activates cellular cAMP signaling through the ABCA1 transporter [37].

Other interactions of APOA1

• ApoA-I FCR was inversely associated with HDL cholesterol level (r=-0.851,P<0.01) and hLCAT activity (r=-0.816, P<0.01) [38].
• Apolipoprotein AI transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice [39].
• Only three significant nonrandom associations were found: APOA1/MspI-3'APOC3/SstI, APOA1/MspI-3'APOA4/XbaI, and APOA4/DraI-APOA4/XbaI [19].
• Glycosphingolipid accumulation inhibits cholesterol efflux via the ABCA1/apolipoprotein A-I pathway: 1-phenyl-2-decanoylamino-3-morpholino-1-propanol is a novel cholesterol efflux accelerator [40].
• However, the effect of apolipoprotein A-I and paraoxonase-1 (PON-1) on phosphatidylcholine oxidation products has not been identified [34].

Analytical, diagnostic and therapeutic context of APOA1

• A new apolipoprotein A1 (APOA1) gene variant has been identified in a family ascertained through a proband undergoing coronary angiography [26].
• The aim of this study was to describe possible modifications of the APOA1, APOC3, and APOA4 gene pool by cross-sectional studies carried out in a healthy ageing population whose ages ranged from 18 to 109 years (800 subjects, 327 males and 473 females, free of clinically manifested disease, and with emato-chemical parameters in the norm) [41].
• NOS3 and ACE, NOS3 and APOA1 were in gametic disequilibrium in the control group [42].
• We investigated whether vasomotor dysfunction develops in aged apoE(-/-), whether the defect was systemic (hypercholesterolemia-dependent) or focal (plaque-related), and the effect of human apolipoprotein AI transgenesis (apoAI/E(-/-)) [43].
• Moderate hyperalphalipoproteinaemia in a Brazilian population is related to lipoprotein lipase activity, apolipoprotein A-I concentration, age and body mass index [44].

References