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At least 19 recordsLinked to original sources
PubMed2001

Apolipoprotein A-V: a novel apolipoprotein associated with an early phase of liver regeneration.

Liver regeneration in response to various forms of liver injury is a complex process, which ultimately results in restoration of the original liver mass and function. Because the underlying mechanisms that initiate this response are still incompletely defined, this study was aimed to identify novel factors. Liver genes that were up-regulated 6 h after 70% hepatectomy (PHx) in the rat were selected by cDNA subtractive hybridization. Besides known genes associated with cell proliferation, several novel genes were isolated. The novel gene that was most up-regulated was further studied. Its mRNA showed a liver-specific expression and encoded a protein comprising 367 amino acids. The mouse and human cDNA analogues were also isolated and appeared to be highly homologous. The human gene analogue was located at an apolipoprotein gene cluster on chromosome 11q23. The protein encoded by this gene had appreciable homology with apolipoproteins A-I and A-IV. Maximal expression of the gene in the rat liver and its gene product in rat plasma was observed 6 h after PHx. The protein was present in plasma fractions containing high density lipoprotein particles. Therefore, we have identified a novel apolipoprotein, designated apolipoprotein A-V, that is associated with an early phase of liver regeneration.

Amino Acid Sequence↗
PubMed2002

Adenoviral overexpression of apolipoprotein A-V reduces serum levels of triglycerides and cholesterol in mice.

Mice lacking ApoA-V, a novel HDL-associated apolipoprotein identified by our group and independently by Pennacchio et al. [Science 294 (2001) 169], were recently shown to be hypertriglyceridemic. To study the role of ApoA-V in triglyceride homeostasis, we compared lipid profiles in mice expressing normal and highly elevated levels of ApoA-V. For this purpose, adenoviral vectors expressing sense or antisense ApoA-V cDNA were constructed. Treatment of mice with sense adenoviral constructs resulted in circa 20-fold higher serum ApoA-V levels compared with mice injected with either PBS or antisense adenoviral constructs. ApoA-V overexpressing mice had markedly decreased (-70%) serum triglyceride levels caused primarily by lowered triglyceride content of the VLDL fraction. Furthermore, in these mice cholesterol levels were found to be lowered in all lipoprotein fractions with the largest mass decrease in the HDL fraction. This resulted in a 40% drop of serum cholesterol content. These findings suggest a role of ApoA-V in regulating levels of circulating triglycerides and cholesterol.

Adenoviridae↗
PubMed2002

Association found between the promoter region polymorphism in the apolipoprotein A-V gene and the serum triglyceride level in Japanese schoolchildren.

The purpose of this study was to assess the influence of single nucleotide polymorphism 3 (SNP3) of the apolipoprotein A-V ( APOA5) gene on the serum triglyceride (TG) level in Japanese schoolchildren. To determine the frequency of the genotype, we analyzed 552 schoolchildren. The frequencies of the T/T, T/C and C/C genotypes of the APOA5 gene were 225 (40.8%), 263 (47.6%) and 64 (11.6%), respectively. The serum TG level was significantly different among the genotypic groups after adjustments for age, gender and obesity index (T/T 71.6+/-34.8 mg/dl, T/C 80.7+/-36.1 mg/dl, C/C 94.4+/-69.4 mg/dl, P<0.0001). The odds ratio (95% confidence interval) for hypertriglyceridemia of the C allele was 2.4 (1.0-6.2). Our data suggested that the T/C promoter region polymorphism of the APOA5 gene appears to be a genetic risk factor for hypertriglyceridemia in Japanese children.

Adolescent↗
PubMed2003

New apolipoprotein A-V: comparative genomics meets metabolism.

The availability of the human genome sequence and the recently completed draft sequences of two major mammalian model species, the mouse (Mus musculus) and the rat (Rattus norvegicus), allow researchers to apply novel approaches for gene identification and characterization, using methods of comparative and functional genomics. Recently, a new gene coding for apolipoprotein A-V was identified in the vicinity of APOA-I/C-III/A-IV cluster on human chromosome 11q23 by comparative sequencing method. In a relatively short time, compelling evidence accumulated for the substantial role of APOA-V in lipid metabolism. Studies in knock-out and transgenic mice revealed that its expression pattern correlates negatively with triglyceride levels. This observation was verified in human population studies in variety of ethnic and age groups. Several single nucleotide polymorphisms were described and particular SNP alleles and haplotypes in the APO A-V gene region were shown to be associated with dyslipidemia. The discovery and characterization of the APO A-V demonstrates current possibilities of the integrative approaches in biology, boosted by the available bioinformatic tools.

Amino Acid Sequence↗
PubMed2003

Apolipoprotein and apolipoprotein receptor genes, blood lipids and disease.

PURPOSE OF REVIEW: Apolipoproteins and their receptors are the main controllers of lipid metabolism and, as such, have a major impact not only on the risk of cardiovascular disease but also on the development and degeneration of the central nervous system. Variations in the genes coding for these apolipoproteins and their receptors and the interaction with the environment determine individual susceptibility to metabolic disturbances, the response to dietary or pharmacological intervention and, finally, to disease. RECENT FINDINGS: This review will focus on recent findings, such as the latest concepts regarding apolipoprotein E in neurodevelopment, the newly identified apolipoprotein A-V and its influence in triglyceride metabolism, and the improved understanding of apolipoprotein A-I and HDL metabolism in the light of the discovery of the ABC family of transporters. Other key aspects of lipoprotein metabolism and cardiovascular disease risk such as apolipoprotein B-100, the LDL receptor, apolipoprotein C-III or apolipoprotein (a) will be updated. SUMMARY: Variations in these genes will be analysed in relation to plasma lipid levels, their interactions with diet, treatment or other environmental stimuli, and their influence on the risk of cardiovascular disease and neurological disorders.

Apolipoproteins↗
PubMed2002

The genetic effect of the apoprotein AV gene on the serum triglyceride level in Japanese.

The newly identified apoprotein AV (apoAV) gene was suggested to have a significant effect on triglyceride (TG) metabolism in Caucasians. We studied the genetic effect of this gene on serum TG in a Japanese population. Participants (481 male and 412 female) were recruited at a health examination. A T/C single nucleotide polymorphism called SNP3 in the 5'-region of the apoAV gene was genotyped as described previously. The frequency of the C allele was much greater in Japanese than in Caucasians (0.34 vs. 0.08). The serum TG level in subjects with the TT genotype was significantly lower than the level in those with TC/CC (1.10, 1.25 and 1.21 mmol/l for TT, TC and CC, respectively, P=0.0003 by ANOVA), while there were no significant differences either in the serum total cholesterol or the low- and high-density lipoprotein cholesterol levels among the three genotypes. Multiple regression analysis indicated that SNP3 had a significant independent effect on the serum TG level in Japanese (P<0.0001). This result indicates that polymorphism in the apoAV gene influence serum TG in populations of different ethnicities.

Apolipoprotein A-V↗
PubMed2003

Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor alpha activators.

The recently discovered APOA5 gene has been shown in humans and mice to be important in determining plasma triglyceride levels, a major cardiovascular disease risk factor. apoAV represents the first described apolipoprotein where overexpression lowers triglyceride levels. Since fibrates represent a commonly used therapy for lowering plasma triglycerides in humans, we investigated their ability to modulate APOA5 gene expression and consequently influence plasma triglyceride levels. Human primary hepatocytes treated with Wy 14,643 or fenofibrate displayed a strong induction of APOA5 mRNA. Deletion and mutagenesis analyses of the proximal APOA5 promoter firmly demonstrate the presence of a functional peroxisome proliferator-activated receptor response element. These findings demonstrate that APOA5 is a highly responsive peroxisome proliferator-activated receptor alpha target gene and support its role as a major mediator for how fibrates reduce plasma triglycerides in humans.

Apolipoprotein A-V↗
PubMed2002

Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels.

The recently identified apolipoprotein A5 gene (APOA5) has been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. We previously identified an APOA5 haplotype (designated APOA5*2) that is present in approximately 16% of Caucasians and is associated with increased plasma triglyceride concentrations. In this report we describe another APOA5 haplotype (APOA5*3) containing the rare allele of the single nucleotide polymorphism c.56C>G that changes serine to tryptophan at codon 19 and is independently associated with high plasma triglyceride levels in three different populations. In a sample of 264 Caucasian men and women with plasma triglyceride concentrations above the 90th percentile or below the 10th percentile, the APOA5*3 haplotype was more than three-fold more common in the group with high plasma triglyceride levels. In a second independently ascertained sample of Caucasian men and women (n=419) who were studied while consuming their self-selected diets as well as after high-carbohydrate diets and high-fat diets, the APOA5*3 haplotype was associated with increased plasma triglyceride levels on all three dietary regimens. In a third population comprising 2660 randomly selected individuals, the APOA5*3 haplotype was found in 12% of Caucasians, 14% of African-Americans and 28% of Hispanics and was associated with increased plasma triglyceride levels in both men and women in each ethnic group. These findings establish that the APOA5 locus contributes significantly to inter-individual variation in plasma triglyceride levels in humans. Together, the APOA5*2 and APOA5*3 haplotypes are found in 25-50% of African-Americans, Hispanics and Caucasians and support the contribution of common human variation to quantitative phenotypes in the general population.

Apolipoprotein A-V↗
PubMed2002

Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides.

Since triglycerides (TG) are a major independent risk factor for coronary heart disease, understanding their genetic and environmental determinants is of major importance. Mouse models indicate an inverse relationship between levels of the newly identified apolipoprotein AV (APOAV) and TG concentrations. We have examined the relative influence of human APOA5 variants on plasma lipids, compared to the impact of variation in APOC3 and APOA4 which lie in the same cluster. 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). 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. APOA4 347SS men had 23% lower TG compared to TT men (P<0.002). Haplotype analysis was carried out to identify TG-raising alleles and included, in addition, four previously genotyped APOC3 SNPs (-2845T>G, -482C>T, 1100C>T, and 3238C>G). The major TG-raising alleles were defined by APOA5 W19 and APOC3 -482T. This suggests that the TG-lowering effect of APOA4 S347 might merely reflect the strong negative linkage disequilibrium with the common alleles of these variants. 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. The molecular mechanisms for these effects remain to be determined.

Apolipoprotein A-V↗
PubMed2001

An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.

Comparison of genomic DNA sequences from human and mouse revealed a new apolipoprotein (APO) gene (APOAV) located proximal to the well-characterized APOAI/CIII/AIV gene cluster on human 11q23. 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. In humans, single nucleotide polymorphisms (SNPs) across the APOAV locus were found to be significantly associated with plasma triglyceride levels in two independent studies. These findings indicate that APOAV is an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease.

Adult↗
PubMed2002

Apolipoprotein A5, a newly identified gene that affects plasma triglyceride levels in humans and mice.

Apolipoprotein A5 (APOA5) is a newly described member of the apolipoprotein gene family whose initial discovery arose from comparative sequence analysis of the mammalian APOA1/C3/A4 gene cluster. Functional studies in mice indicated that alteration in the level of APOA5 significantly affected plasma triglyceride concentrations. Mice that overexpressed human APOA5 displayed significantly reduced triglycerides, whereas mice that lacked apoa5 had a large increase in this lipid parameter. Studies in humans have also suggested an important role for APOA5 in determining plasma triglyceride concentrations. In these experiments, polymorphisms in the human gene were found to define several common haplotypes that were associated with significant changes in triglyceride concentrations in multiple populations. Several separate clinical studies have provided consistent and strong support for the effect with 24% of whites, 35% of blacks, and 53% of Hispanics who carry APOA5 haplotypes associated with increased plasma triglyceride levels. In summary, APOA5 represents a newly discovered gene involved in triglyceride metabolism in both humans and mice whose mechanism of action remains to be deciphered.

Adult↗
PubMed2003

Genetic analysis of a polymorphism in the human apoA-V gene: effect on plasma lipids.

Recent discovery and characterization of APOAV suggests a role in metabolism of triglyceride (TG)-rich lipoproteins. Previously, variation at the APOAV locus was shown to modestly influence plasma TGs in normolipidemic samples. The aims of this study were to assess the effects of a polymorphism in APOAV (T-1131C) in terms of its frequency among three dyslipidemic populations and a control population, differences of allele frequency across available ethnic groups, and associations with specific lipoprotein TG and cholesterol compartments. We found a striking elevation in the frequency of the rare allele in a Chinese population (P = 0.0002) compared with Hispanic and European populations. The rare allele of the polymorphism was associated with elevated plasma TG (P = 0.012), VLDL cholesterol (P = 0.0007), and VLDL TG (P = 0.012), LDL TG (P = 0.003), and HDL TG (P = 0.016). Linear regression models predict that possession of the rare allele elevates plasma TG by 21 mg/dl (P = 0.009) and VLDL cholesterol by 8 mg/dl (P = 0.0001), and reduces HDL cholesterol by 2 mg/dl (P = 0.017). The association of the polymorphism with altered lipoprotein profiles was observed in combined hyperlipidemia, hypoalphalipoproteinemia, and hyperalphalipoproteinemia, and in controls. These findings indicate that APOAV is an important determinant of plasma TG and lipoprotein cholesterol, and is potentially a risk factor for cardiovascular disease.

Adult↗
PubMed2025

Pathogenicity assessment of genetic variants identified in patients with severe hypertriglyceridemia: Novel cases of familial chylomicronemia syndrome from the Dyslipidemia Registry of the Spanish Atherosclerosis Society.

PURPOSE: Genetic testing is required to confirm a diagnosis of familial chylomicronemia syndrome (FCS). We assessed the pathogenicity of variants identified in the FCS canonical genes to diagnose FCS cases. METHODS: 245 patients with severe hypertriglyceridemia underwent next-generation sequencing. Preliminary variant pathogenicity criteria and classification, based on the American College of Medical Genetics and Genomics guidelines, were obtained online and verified. Phenotype evaluation was based on lipoprotein lipase activity deficiency, a clinical score, and/or type I hyperlipoproteinemia determined in 25 patients. RESULTS: Twenty-four biallelic variants were analyzed. Evidence-based criteria allowed the reclassification of 8 likely pathogenic (LP) variants in the LPL, APOA5, and LMF1 genes into pathogenic (P) and the change of 2 variants of uncertain significance (VUS) to LP. Conversely, 2 variations in LMF1 remained as VUS. Additionally, 1 variant in LPL and 2 in GPIHBP1 were likely benign. Twenty FCS cases had biallelic P/LP variants and 1 patient, with an FCS phenotype, harbored biallelic VUS. FCS was excluded from 4 patients with pathogenic/likely benign combinations. CONCLUSION: The analysis of the clinical and biochemical features of patients with variants in the FCS canonical genes allowed a confident variant classification that helped in the diagnosis of novel FCS cases.

Humans↗
PubMed1999

Utilization of intestinal triglyceride-rich lipoproteins in mammary gland of cows.

Elution profiles of total lipoproteins, apolipoprotein B (apoB) concentrations in lipoproteins, and plasma triglyceride (TG) levels were examined in early-, late-, and non-lactating cows. Additionally, arteriovenous (A-V) differences were also measured to elucidate the uptake of TG and apoB-containing lipoproteins in mammary gland. Non-lactating cows showed three major peaks corresponding to triglyceride-rich lipoprotein (TRL), low density lipoprotein (LDL), and high density lipoprotein (HDL) fraction, whereas both early- and late-lactating cows revealed two peaks corresponding to TRL and HDL. The peak area of TRL in early- and late-lactating cows were significantly (p < 0.05) smaller than that in non-lactating cows. The plasma TG levels and apoB-48 concentrations of TRL in early- and late-lactating cows were also significantly (p < 0.01) lower. Furthermore, early lactating cows showed significantly (p < 0.05) larger A-V differences in both plasma TG and apoB-48 concentration of TRL than those in late- and non-lactating cows. These results suggested that TG in exogenous (intestinal) TRL was utilized for milk fat synthesis in lactating mammary gland of cows by the receptor-mediated uptake.

Animals↗
PubMed2001

Effect of apolipoprotein E genotype on cerebral autoregulation during cardiopulmonary bypass.

BACKGROUND AND PURPOSE: The presence of the apolipoprotein E epsilon4 (apoE4) allele has been associated with cognitive decline after cardiac surgery. We compared autoregulation of cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO(2)), and arterial-venous oxygen content difference [C(A-V)O(2)], during cardiopulmonary bypass (CPB) in patients with and without the apoE4 allele to help define the mechanism of association with cognitive decline. METHODS: One hundred fifty-four patients underwent coronary artery bypass grafting with CPB, nonpulsatile flow, and alpha-stat management. CBF was measured by using (133)Xe washout methods. C(A-V)O(2), CMRO(2), and oxygen delivery were calculated. Pressure-flow autoregulation was tested by using 2 CBF measurements at stable hypothermia: the first at stable mean arterial pressure (MAP) and the second 15 minutes later, when MAP had increased or decreased >/=20%. Metabolism-flow autoregulation was tested by varying the temperature and measuring the coupling of CBF and CMRO(2). RESULTS: In patients with (n=41) or without (n=113) the apoE4 allele, there were no differences in CBF, CMRO(2), C(A-V)O(2), pressure-flow and metabolism-flow autoregulation corrected for age, gender, non-insulin-dependent diabetes, hemoglobin, CPB time, and temperature. CONCLUSIONS: We conclude that apoE genotype does not affect global CBF and oxygen delivery/extraction during CPB, which suggests that other mechanisms are responsible for the apoE isoform-related neurocognitive dysfunction seen in patients undergoing CPB.

Apolipoproteins E↗