Search

BackgroundNo study has evaluated whether genetic factors are associated with longevity in African Americans or Hispanics, and it is unclear whether genetic factors are associated with healthy aging.MethodsIn this prospective study, we determined whether 14 genetic variants previously associated with longevity in genome-wide association studies were associated with survival to ages 85 and 90 in 11,053 postmenopausal white, African American, and Hispanic women from the Women's Health Initiative. The associations of these variants with healthy aging, defined as survival to age 85 without chronic diseases or disability, were also determined.ResultsAmong white women, three single nucleotide polymorphisms (SNPs) (rs2075650 [TOMM40], rs4420638 [APOC1], and rs429358 [APOE]) were significantly associated with survival to 90 years after correction for multiple testing (p < .001); rs4420638 and rs429358 were also significantly associated with healthy aging (p = .02). In African American women, no SNP was associated with longevity. In Hispanic women, 7 SNPs in linkage disequilibrium with a novel SNP, rs2149954, recently identified as being associated with increased longevity in a European population, were significantly associated with decreased survival to age 85 for carriers of the T versus C allele (p = .04). The association with decreased longevity was explained by higher risk of coronary heart disease in carriers of the T allele. There were no associations between FOXO3A SNPs and longevity in the analyses. In a meta-analysis, rs2075650 and rs429358 were significantly associated with longevity.ConclusionsFuture studies are needed to identify novel loci associated with longevity in African American and Hispanic women to determine biologic pathways regulating life span in these groups.

BackgroundNo study has evaluated whether genetic factors are associated with longevity in African Americans or Hispanics, and it is unclear whether genetic factors are associated with healthy aging.MethodsIn this prospective study, we determined whether 14 genetic variants previously associated with longevity in genome-wide association studies were associated with survival to ages 85 and 90 in 11,053 postmenopausal white, African American, and Hispanic women from the Women's Health Initiative. The associations of these variants with healthy aging, defined as survival to age 85 without chronic diseases or disability, were also determined.ResultsAmong white women, three single nucleotide polymorphisms (SNPs) (rs2075650 [TOMM40], rs4420638 [APOC1], and rs429358 [APOE]) were significantly associated with survival to 90 years after correction for multiple testing (p < .001); rs4420638 and rs429358 were also significantly associated with healthy aging (p = .02). In African American women, no SNP was associated with longevity. In Hispanic women, 7 SNPs in linkage disequilibrium with a novel SNP, rs2149954, recently identified as being associated with increased longevity in a European population, were significantly associated with decreased survival to age 85 for carriers of the T versus C allele (p = .04). The association with decreased longevity was explained by higher risk of coronary heart disease in carriers of the T allele. There were no associations between FOXO3A SNPs and longevity in the analyses. In a meta-analysis, rs2075650 and rs429358 were significantly associated with longevity.ConclusionsFuture studies are needed to identify novel loci associated with longevity in African American and Hispanic women to determine biologic pathways regulating life span in these groups.

BackgroundMultiple genetic loci are associated with clinical cardiovascular (CV) disease and individual CV risk factors. Individuals with ideal levels of all major CV risk factors have very low risk for CV disease morbidity or mortality. Ideal levels of risk factors can be attained by lifestyle modifications; however, little is known about gene variants associated with ideal CV health. Our objective was to carry out a genome-wide association study on the trait.Methods and resultsWe examined 2 dichotomous phenotypes of ideal CV health-clinical (untreated cholesterol <200 mg/dL, untreated blood pressure <120/<80, not diabetic) and clinical+behavioral (clinical plus: not a current smoker, body mass index <25 kg/m(2))-among white participants aged 50±5 years. We performed a meta-analysis of 4 genome-wide association studies (total n=11,708) from the MESA, CARDIA, ARIC, and Framingham Heart Study cohorts. We identified a single-nucleotide polymorphism (rs445925) in the APOC1/APOE region that was associated with clinical ideal CV health at genome-wide level of significance (P<2.0 × 10(-9)). The significance of this region was validated using exome chip genotyping. The association with ideal CV health was attenuated after adjusting for low-density lipoprotein cholesterol.ConclusionA common single-nucleotide polymorphism in the APOC1/APOE region, previously found to be associated with protective levels of cholesterol and lower CV risk, may be associated with ideal health. In future replication studies, larger sample sizes may be needed to detect loci with more modest effects on ideal CV health. In addition to the important impact of lifestyle modifications, we have identified evidence for gene variation that plays a role in ideal CV health.

Apolipoproteins (apo) C-I and C-III are known to inhibit lipoprotein lipase (LPL) activity, but the molecular mechanisms for this remain obscure. We present evidence that either apoC-I or apoC-III, when bound to triglyceride-rich lipoproteins, prevent binding of LPL to the lipid/water interface. This results in decreased lipolytic activity of the enzyme. Site-directed mutagenesis revealed that hydrophobic amino acid residues centrally located in the apoC-III molecule are critical for attachment to lipid emulsion particles and consequently inhibition of LPL activity. Triglyceride-rich lipoproteins stabilize LPL and protect the enzyme from inactivating factors such as angiopoietin-like protein 4 (angptl4). The addition of either apoC-I or apoC-III to triglyceride-rich particles severely diminished their protective effect on LPL and rendered the enzyme more susceptible to inactivation by angptl4. These observations were seen using chylomicrons as well as the synthetic lipid emulsion Intralipid. In the presence of the LPL activator protein apoC-II, more of apoC-I or apoC-III was needed for displacement of LPL from the lipid/water interface. In conclusion, we show that apoC-I and apoC-III inhibit lipolysis by displacing LPL from lipid emulsion particles. We also propose a role for these apolipoproteins in the irreversible inactivation of LPL by factors such as angptl4.

Apolipoprotein CI (apoCI) has been suggested to influence HDL metabolism by activation of LCAT and inhibition of HL and CETP. However, the effect of apoCI on scavenger receptor BI (SR-BI)-mediated uptake of HDL-cholesteryl esters (CE), as well as the net effect of apoCI on HDL metabolism in vivo is unknown. Therefore, we evaluated the effect of apoCI on the SR-BI-mediated uptake of HDL-CE in vitro and determined the net effect of apoCI on HDL metabolism in mice. Enrichment of HDL with apoCI dose-dependently decreased the SR-BI-dependent association of [3H]CE-labeled HDL with primary murine hepatocytes, similar to the established SR-BI-inhibitors apoCIII and oxLDL. ApoCI deficiency in mice gene dose-dependently decreased HDL-cholesterol levels. Adenovirus-mediated expression of human apoCI in mice increased HDL levels at a low dose and increased the HDL particle size at higher doses. We conclude that apoCI is a novel inhibitor of SR-BI in vitro and increases HDL levels in vivo. © 2008 Elsevier Inc. All rights reserved.

Mice that overexpress human apolipoprotein C-I (apoC-I) homozygously (APOC1+/+ mice) are protected against obesity and show cutaneous abnormalities. Although these effects can result from our previous observation that apoC-I inhibits FFA generation by LPL, we have also found that apoC-I impairs the uptake of a FFA analog in adipose tissue. In this study, we tested the hypothesis that apoC-I interferes with cellular FFA uptake independent of LPL activity. The cutaneous abnormalities of APOC1+/+ mice were not affected after transplantation to wild-type mice, indicating that locally produced apoC-I prevents lipid entry into the skin. Subsequent in vitro studies with apoC-Ideficient versus wild-type macrophages revealed that apoC-I reduced the cell association and subsequent esterification of [3H]oleic acid by ∼35% (P < 0.05). We speculated that apoC-I binds FFA extracellularly, thereby preventing cell association of FFA. We showed that apoC-I was indeed able to mediate the binding of oleic acid to otherwise protein-free VLDL-like emulsion particles involving electrostatic interaction. We conclude that apoC-I binds FFA in the circulation, thereby reducing the availability of FFA for uptake by cells. This mechanism can serve as an additional mechanism behind the resistance to obesity and the cutaneous abnormalities of APOC1+/+ mice. Copyright ©2007 by the American Society for Biochemistry and Molecular Biology, Inc.

Obese obob mice with strong overexpression of the human apolipoprotein C1 (APOC1) exhibit excessive free fatty acid (FFA) and triglyceride (TG) levels and severely reduced body weight (due to the absence of subcutaneous adipose tissue) and skin abnormalities. To evaluate the effects of APOC1 overexpression on hepatic and peripheral insulin sensitivity in a less-extreme model, we generated obob mice with mild overexpression of APOC1 (obob/APOC1+/-) and performed hyperinsulinemic clamp analysis. Compared with obob littermates, obob/APOC1+/- mice showed reduced body weight (-25%) and increased plasma levels of TG (+632%), total cholesterol (+134%), FFA (+65%), glucose (+73%, and insulin (+49%). Hyperinsulinemic clamp analysis revealed severe whole-body and hepatic insulin resistance in obob/APOC1+/- mice and, in addition, increased hepatic uptake of FFA and hepatic TG content. Treatment of obob/APOC1+/- mice with rosiglitazone strongly improved whole-body insulin sensitivity as well as hepatic insulin sensitivity, despite a further increase of hepatic fatty acid (FA) uptake and a panlobular increase of hepatic TG accumulation. We conclude that overexpression of APOC1 prevents rosiglitazone-induced peripheral FA uptake leading to severe hepatic steatosis. Interestingly, despite rosiglitazone-induced hepatic steatosis, hepatic insulin sensitivity improves dramatically. We hypothesize that the different hepatic fat accumulation and/or decrease in FA intermediates has a major effect on the insulin sensitivity of the liver. Chemicals / CAS: glucose, 50-99-7, 84778-64-3; insulin, 9004-10-8; rosiglitazone, 122320-73-4, 155141-29-0; Apolipoprotein C-I; Apolipoproteins C; Blood Glucose; Fatty Acids; Insulin, 11061-68-0

Transgenic mice overexpressing human APOE*3Leiden are highly susceptible to diet-induced hyperlipoproteinemia and atherosclerosis due to a defect in hepatic uptake of remnant lipoproteins. In addition to the human APOE*3Leiden gene, these mice carry the human APOC1 gene (APOE*3Leiden- C1). To investigate the possible effect of simultaneous expression of the human APOC1 gene, we examined the phenotypic expression in these APOE*3Leiden-C1 mice in relation to transgenic mice expressing the APOE*3Leiden gene without the APOC1 gene (APOE*3Leiden-HCR), APOE*3Leiden-C1 and APOE*3Leiden-HCR mice had comparable liver expression for the APOE*3Leiden transgene and high total cholesterol levels on a sucrose-based diet compared with control mice (4.3 and 4.3 versus 2.1 mmol/L). In addition, on this diet APOE*3Leiden-C1 mice displayed significantly higher serum triglyceride levels than APOE*3Leiden-HCR mice and control mice (4.4 versus 0.6 and 0.2 mmol/L). Elevated triglyceride and cholesterol levels were mainly in the VLDL-sized lipoproteins. In vivo turnover studies with endogenously triglyceride-labeled VLDL showed a reduced VLDL triglyceride fractional catabolic rate for APOE*3Leiden-C1 and APOE*3Leiden-HCR mice compared with control mice (3.5 and 11.0 versus 20.4 pools per hour). To study whether the difference in fractional catabolic rates between the two transgenic strains was due to an inhibiting effect of apoC1 on the extrahepatic lipolysis or hepatic-mediated uptake of VLDL, turnover experiments were performed in functionally hepatectomized mice. Strikingly, both APOE*3Leiden-C1 and APOE*3Leiden-HCR mice showed a decreased lipolytic rate of VLDL triglyceride in the extrahepatic circulation compared with control mice (1.5 and 1.8 versus 6.3 pools per hour). We conclude that next to an impaired hepatic uptake, overexpression of the APOE*3Leiden gene influences the extrahepatic lipolysis of VLDL triglycerides, whereas simultaneous overexpression of the APOC1 gene leads to

Labeling of apolipoprotein C-I by the Bolton and Hunter reagent allowed a study of the kinetics of this peptide in normolipidemic human volunteers. After its intravenous injection the appearance of radioactivity of the labeled apoprotein was followed in plasma, lipoprotein fractions, and urine for 15 days. Apolipoprotein C-I was quickly associated with HDL and to a smaller extent with VLDL in in vitro and in vivo incubation. Kinetic parameters of apolipoprotein C-I were compared with those of apo A-I. Fractional catabolic rates are respectively 0.422 ± 0.044 vs 0.240 ± 0.003 pools/day, residence times through the whole system 3.24 ± 0.27 vs 6.31 ± 0.27 days and production rates 1.79 ± 0.18 vs 13.2 ± 2.1 mg/kg · day. Two explanations for these differences are proposed. © 1986., SCOPUS: ar.j, info:eu-repo/semantics/published

Labeling of apolipoprotein C-I by the Bolton and Hunter reagent allowed a study of the kinetics of this peptide in normolipidemic human volunteers. After its intravenous injection the appearance of radioactivity of the labeled apoprotein was followed in plasma, lipoprotein fractions, and urine for 15 days. Apolipoprotein C-I was quickly associated with HDL and to a smaller extent with VLDL in in vitro and in vivo incubation. Kinetic parameters of apolipoprotein C-I were compared with those of apo A-I. Fractional catabolic rates are respectively 0.422 ± 0.044 vs 0.240 ± 0.003 pools/day, residence times through the whole system 3.24 ± 0.27 vs 6.31 ± 0.27 days and production rates 1.79 ± 0.18 vs 13.2 ± 2.1 mg/kg · day. Two explanations for these differences are proposed. © 1986., SCOPUS: ar.j, info:eu-repo/semantics/published