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To investigate the relationship between SNPs reported in previous studies and the blood lipid level in the Tibetan population. Random cluster sampling was employed in 5 areas (Lhasa, Shigatse, Shannan, Nagqu, and Nyingchi). The levels of cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from blood samples were determined and DNA was extracted for genotyping and statistical analyses. Among 1 318 subjects aged >18 years enrolled in this study, 367 had dyslipidemia with a prevalence of 27.8%, of whom dyslipidemia males accounted for 33.1% and dyslipidemia females -24.5%. Results of the correlation analysis between all SNPs and TG showed that the SNPs of rs714052 and rs964184 were related to the serum TG level. Subjects with rs714052 CC genotype had the lowest TG level, and the highest TG level was found in those with rs714052 TT genotype. The serum TG level in individuals with TC genotype lied in between the above two population groups. Subjects with rs964184 CC genotype had the lowest TG level, and the highest serum TG level was noted in those with rs964184 GG genotype. Several SNPs were found to be related to the serum TG level in the Tibetan population. The APOA5 gene and MLXIPL gene may be closely associated with the serum TG level in this ethnic population group. Show less

Apolipoprotein A-V plays an important role in reducing plasma triglyceride levels. We hypothesized that expression of apoA-V would inhibit atherogenesis in apoE(-/-) mice fed chow diet which is a known model of hypercholesterolemia. Our aim was to study this protective effect and to explore possible mechanisms. ApoA-V(+/+)ApoE(-/-) mice expressing human apolipoprotein A-V (hapoA-V) were generated and compared to apoE(-/-) mice. Atherosclerotic aortic sinus lesion area was 70% smaller in hapoA-V(+/+)apoE(-/-). This was accompanied by a 58% reduction in lesion macrophage content. Furthermore, advanced atherosclerotic lesions in hapoA-V(+/+)apoE(-/-) mice showed features of a more stable plaque, manifested by 59% and 37% higher collagen and α-actin content, respectively. Plasma triglyceride and cholesterol levels in hapoA-V(+/+)apoE(-/-) mice were 47% and 33% lower, respectively. These were associated with a 33% reduction in very low density lipoprotein triglyceride production and 2-fold acceleration in triglyceride-rich lipoprotein clearance in hapoA-V(+/+)apoE(-/-) mice. In addition, hapoA-V(+/+)apoE(-/-) mice showed enhanced insulin sensitivity (25% and 15% improvement in glucose tolerance and insulin responsiveness, respectively). Finally, hapoA-V(+/+)apoE(-/-) displayed a milder systemic inflammatory response compared to apoE(-/-) mice, manifested by 22%, 65% and 15% lower plasma levels of TNFα, IL-1β and IL-6, respectively. We showed that human apolipoprotein A-V is a potent modulator of atherosclerosis in mice through multiple modes of action. These findings may identify apoA-V as a potential therapeutic target for treatment of atherosclerosis. Show less

Apolipoprotein A5 (apoA5), an important determinant of plasma triglyceride (TG) levels, has been recently reported to modulate TG metabolism in hepatocytes. In this study, we investigated whether apoA5 can be internalized by adipocytes and regulate cellular TG storage. Human preadipocytes, derived from subcutaneous adipose tissue of patients undergoing abdominal surgery, were differentiated into mature adipocytes. Pulse-chase experiments revealed that apoA5 was internalized into human adipocytes, and ∼70% of the apoA5 internalized during the pulse remained intracellular within a 24-h chase, while 30% was degraded. Preincubation with heparin and the receptor-associated protein, both of which prevented the apoA5 interaction with members of the low-density lipoprotein receptor gene family, markedly reduced the uptake of apoA5 by 61% and 52%, respectively, which were subsequently confirmed by Western blot analysis. Using confocal microscopy, we demonstrated that labeled apoA5 surrounded lipid droplets in human adipocytes and colocalized with the known lipid droplet protein perilipin. Importantly, treatment of adipocytes with apoA5 significantly decreased cellular TG storage. In conclusion, apoA5 can be internalized by human adipocytes and may act as a novel regulator to control TG storage in human adipocytes. Show less

The association between polymorphism -1131T/C in the promoter region of apolipoprotein A5 (APOA5) and ischemic stroke and plasma triglyceride (TG) levels remains controversial. To better clarify the association between APOA5-1131T/C and risk of ischemic stroke and plasma TG levels, we performed a meta-analysis to examine the allele and genotype of APOA5-1131T/C polymorphism in ischemic stroke cases and controls. Based on the search of PubMed, Embase, MEDLINE, CNKI (National Knowledge Infrastructure) and CBM (Chinese BioMedical Literature Database) databases, we identified and abstracted outcome data from all articles to evaluate the association between APOA5 and ischemic stroke/plasma TG levels. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were performed in dominant model (CC + TC vs. TT), recessive model (CC vs. TC + TT), homozygote comparison (CC vs. TT) and heterozygote comparison (TC vs. TT). The association between dominant model (CC + TC vs. TT) and plasma TG/total cholesterol/high-density lipoprotein cholesterol levels was measured by a weighted mean difference (WMD) with its corresponding 95% CI. To evaluate the ethnicity-specific effects, subgroup analyses were performed by ethnic group. A meta-analysis containing 2,294 ischemic stroke cases and 1,858 controls from 8 case-control studies was performed. The results showed that APOA5-1131T/C polymorphism was significantly associated with ischemic stroke in all comparison models (CC + TC vs. TT, OR = 1.70, 95% CI = 1.24-2.32; CC vs. TC + TT, OR = 1.36, 95% CI = 0.98-1.90; CC vs. TT, OR = 1.73, 95% CI = 1.34-2.23; TC vs. TT, OR = 1.67, 95% CI = 1.19-2.36). On subgroup analysis by ethnicity, similarly significant associations were found in both Asians and Europeans, and the Europeans possessed a higher risk of ischemic stroke, especially in CC versus TT model (OR = 4.47, 95% CI = 1.33-15.06). Significant association between the C allele and elevated TG levels was detected in both ischemic stroke cases and controls; the TG levels were higher in the ischemic stroke cases and controls carrying the APOA5-1131C allele than in the noncarriers (CC + TC vs. TT, cases WMD = 0.43, 95% CI = 0.27-0.59; controls WMD = 0.51, 95% CI = 0.35-0.66). Similar within-group comparison of the total cholesterol and high-density lipoprotein cholesterol levels did not show any difference. Our meta-analysis revealed that the APOA5-1131T/C polymorphism is associated with a significant risk of ischemic stroke and elevated TG levels. The CC genotype and C allele might be a genetic risk factor that increases susceptibility of ischemic stroke and elevates plasma TG levels, and might be a useful target for clinical therapeutic intervention. Show less

Although low-density lipoprotein cholesterol (LDL-C) is the main lipid target for cardiovascular risk reduction, recent studies suggest that other lipid indicies are also associated with vascular events. We hypothesized that the association of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) with atherosclerotic stroke (AS) differs depending on LDL-C levels. Data prospectively collected on subjects admitted with acute ischemic stroke to a university medical center were analyzed. We divided the patients into AS and non-atherosclerotic stroke (NAS) groups and independent association of lipid parameters and genetic influences of apolipoprotein A5 (ApoA5) polymorphisms with AS were evaluated. Of 268 patients, 160 (59.7%) were classified with AS and 108 (40.3%) were classified with NAS. Vascular risk factors were more prevalent in AS patients than in those with NAS; additionally, AS patients' anthropometric indexes and laboratory findings showed that they were prone to atherosclerosis. AS was independently associated with fasting TG (OR per 10 mg/dL increase, 1.38; 95% CI, 1.16-1.64; OR for highest vs. lowest tertile, 12.85; 95% CI, 3.31-49.85), HDL-C (OR per 10 mg/dL increase, 0.61; 95% CI, 0.42-0.88; OR for lowest vs. highest tertile, 4.28; 95% CI, 1.16-15.86), and nonfasting TG (OR per 10 10 mg/dL increase, 1.25; 95% CI, 1.11-1.42; OR for highest vs. lowest tertile, 8.20; 95% CI, 1.98-33.88) only among patients with LDL <100 mg/dL. No interaction was observed between fasting and nonfasting TG and ApoA5 polymorphisms. In conclusion, fasting and nonfasting TG and HDL-C were associated with AS only when patients had low levels of LDL-C. Non-LDL-C may have an additional role in addition to the LDL-C levels in AS development. Show less

Acute coronary syndromes (ACSs) are clinically cardiovascular events associated with dyslipidemia in common. Single nucleotide polymorphisms (SNPs) and haplotypes in the APOA1/C3/A5 gene cluster are associated with diabetes and familial combined hyperlipidaemia (FCH). Little is known about whether the polymorphisms in these genes affect lipid homeostasis in patients with ACSs. The present paper aimed to examine these associations with 4 SNPs in the APOA1 -75G > A, the APOC3 -455T > C, and APOA5 -1131T > C, c.553G > T variant to ACSs in Chinese Han. Chinese Han of 229 patients with ACSs and 254 unrelated controls were analyzed. Four SNPs in APOA1/C3/A5 cluster were genotyped and lipid was determined. Our data show that minor allelic frequencies of APOC3 -455T > C, APOA5 -1131T > C, and c.553G > T polymorphisms in patients with ACSs were significantly higher than control group (P < 0.05). Furthermore, the 3 polymorphic sites were strongly of linkage disequilibrium, and minor alleles of 3 SNP sites had higher TG level than wild alleles (P < 0.05), APOC3 -455C and APOA5 c.553T allele carriers also had lower level of HDL-C. The minor alleles of APOC3 -455T > C, APOA5 -1131T > C, and c.553G > T polymorphisms are closely associated with ACSs. Show less

Recent genome-wide association scans (GWAS) and meta-analysis studies on European populations have identified many genes previously implicated in lipid regulation. Validation of these loci on different global populations is important in determining their clinical relevance, particularly for development of novel drug targets for treating and preventing diabetic dyslipidemia and coronary artery disease (CAD). In an attempt to replicate GWAS findings on a non-European sample, we examined the role of six of these loci (CELSR2-PSRC1-SORT1 rs599839; CDKN2A-2B rs1333049; BUD13-ZNF259 rs964184; ZNF259 rs12286037; CETP rs3764261; APOE-C1-C4-C2 rs4420638) in our Asian Indian cohort from the Sikh Diabetes Study (SDS) comprising 3,781 individuals (2,902 from Punjab and 879 from the US). Two of the six SNPs examined showed convincing replication in these populations of Asian Indian origin. Our study confirmed a strong association of CETP rs3764261 with high-density lipoprotein cholesterol (HDL-C) (p = 2.03×10(-26)). Our results also showed significant associations of two GWAS SNPs (rs964184 and rs12286037) from BUD13-ZNF259 near the APOA5-A4-C3-A1 genes with triglyceride (TG) levels in this Asian Indian cohort (rs964184: p = 1.74×10(-17); rs12286037: p = 1.58×10(-2)). We further explored 45 SNPs in a ∼195 kb region within the chromosomal region 11q23.3 (encompassing the BUD13-ZNF259, APOA5-A4-C3-A1, and SIK3 genes) in 8,530 Asian Indians from the London Life Sciences Population (LOLIPOP) (UK) and SDS cohorts. Five more SNPs revealed significant associations with TG in both cohorts individually as well as in a joint meta-analysis. However, the strongest signal for TG remained with BUD13-ZNF259 (rs964184: p = 1.06×10(-39)). Future targeted deep sequencing and functional studies should enhance our understanding of the clinical relevance of these genes in dyslipidemia and hypertriglyceridemia (HTG) and, consequently, diabetes and CAD. Show less

We previously showed that the -1131T→C polymorphism (rs662799) of the apolipoprotein A-V gene (APOA5) and the C→T polymorphism (rs6929846) of the butyrophilin, subfamily 2, member A1 gene (BTN2A1) were significantly associated with an increased serum concentration of triglycerides, a decreased serum concentration of high density lipoprotein (HDL)-cholesterol, and the prevalence of metabolic syndrome (MetS) in Japanese individuals. The purpose of the present study was to examine whether these polymorphisms synergistically affect the prevalence of dyslipidemia and MetS in East Asian populations. The study populations comprised 7471 Japanese and 3529 Korean individuals in the dyslipidemia study, and 3474 Japanese and 1671 Korean individuals in the MetS study. Multivariable logistic regression analysis of combined genotypes with adjustment for age, gender and diabetes mellitus revealed that rs662799 and rs6929846 significantly and synergistically affected dyslipidemia. Japanese or Korean individuals with the C allele of APOA5 and the T allele of BTN2A1 had a 2.05- or 1.92-fold increased risk for hypertriglyceridemia and a 1.82- or 1.56-fold increased risk for hypo-HDL-cholesterolemia, respectively, compared to those with the TT genotype of APOA5 and the CC genotype of BTN2A1. Similar analysis with adjustment for age and gender revealed that Japanese individuals, but not Korean individuals, with the C allele of APOA5 and the T allele of BTN2A1 had a 2.87-fold increased risk for MetS compared to those with the TT genotype of APOA5 and the CC genotype of BTN2A1. Genetic variants of APOA5 and BTN2A1 may synergistically affect the prevalence of dyslipidemia in East Asian populations and of MetS in Japanese individuals. Show less

This study examined the associations of the APOA5 T-1131C (rs662799), G553T (Cys185Gly, rs2075291), GCK G-30A (rs1799884), GCKR A/G at intron 16 (rs780094) and T1403C (Leu446Pro, rs1260326) polymorphisms with serum lipid and glucose levels in Japanese, considering lifestyle factors. Study subjects were 2,191 participants (aged 35-69 years, 1,159 males) enrolled in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. Dyslipidemia was defined as fasting serum triglycerides (FTG) ≥ 150 mg/dL and/or HDL-cholesterol (HDL-C) < 40 mg/dL, while dysglycemia was as fasting blood sugar (FBS) ≥ 110 mg/dL. When those with APOA5 -1131 T/T or 553 G/G were defined as references, those with APOA5 -1131 T/C, C/C or 553 G/T, T/T demonstrated significantly elevated risk of dyslipidemia (age- and sex-adjusted odds ratio: 1.77 [95% confidence interval:1.39-2.27], 3.35 [2.41-4.65], 2.23 [1.64-3.02] and 13.78 [3.44-55.18], respectively). Evaluation of FTG, HDL-C or FBS levels according to the genotype revealed that FTG and HDL-C levels were significantly associated with the APOA5 T-1131C and G553T polymorphisms, FTG with the GCKR rs780094 and rs1260326 polymorphisms, and FBS with the GCKR rs780094 and rs1260326 polymorphisms. Moreover, a significant positive interaction between APOA5 553 G/T+T/T genotypes and fat intake ≥ 25% of total energy for the risk of dyslipidemia was observed. Our cross-sectional study confirmed the essential roles of the polymorphisms of the APOA5, GCK and GCKR in the lipid or glucose metabolism disorders, and suggested the importance of fat intake control in the individualized prevention of dyslipidemia. Show less

Severe hypertriglyceridemia is associated with acute pancreatitis and can be a manifestation of lipoprotein lipase (LPL) deficiency. It is associated with a spectrum of disorders, ranging from heterozygous LPL deficiency allied with environmental factors to rare severe cases of homozygous LPL deficiency. The genes associated with reduced LPL activity include LPL, its cofactor apoC-2, a controlling protein apoA-5 and the LPL receptor GPI-HBP1. The effects of mutations are exacerbated by environmental factors such as diet, pregnancy and insulin resistance. Treatment of clinical LPL deficiency is by ultra-low-fat diet along with the use of fibrates, omega-3 fatty acids, niacin, statins and insulin-sensitizing therapies, depending on the extent of residual LPL activity. Novel therapies that target lipoprotein particle assembly through the antisense oligonucleotides or by interference with triglyceride-loading microsomal transport protein inhibitors offer new potential options for treating hypertriglyceridemia. Show less

Vitamin D and serum lipid levels are risk factors for cardiovascular disease. We sought to determine if vitamin D (25OHD) interacts at established lipid loci potentially explaining additional variance in lipids. 1060 individuals from Utah families were used to screen 14 loci for SNPs potentially interacting with dietary 25OHD on lipid levels. Identified putative interactions were evaluated for (1) greater effect size in subsamples with winter measures, (2) replication in an independent sample, and (3) lack of gene-environment interaction for other correlated dietary factors. Maximum likelihood models were used to evaluate interactions. The replicate sample consisted of 2890 individuals from the Family Heart Study. Putative 25OHD receptor binding site modifying SNPs were identified and allele-specific, 25OHD-dependent APOA5 promoter activity examined using luciferase expression assays. An additional sample with serum 25OHD measures was analyzed. An rs3135506-25OHD interaction influencing HDL-C was identified. The rs3135506 minor allele was more strongly associated with low HDL-C in individuals with low winter dietary 25OHD in initial and replicate samples (p=0.0003 Utah, p=0.002 Family Heart); correlated dietary factors did not explain the interaction. SNP rs10750097 was identified as a putative causative polymorphism, was associated with 25OHD-dependent changes in APOA5 promoter activity in HEP3B and HEK293 cells (p<0.01), and showed similar interactions to rs3135506 in family cohorts. Linear interactions were not significant in samples with serum 25OHD measures; however, genotype-specific differences were seen at deficient 25OHD levels. A 25OHD receptor binding site modifying APOA5 promoter polymorphism is associated with lower HDL-C in 25OHD deficient individuals. Show less

Various studies have linked different genetic single nucleotide polymorphisms (SNPs) to different blood lipids (BL), but whether these "connections" were identified using cross-sectional or longitudinal (i.e., changes over time) designs has received little attention. Cross-sectional and longitudinal assessments of BL [total, high-, low-density lipoprotein cholesterol (TC, HDL, LDL), triglycerides (TG)] and non-genetic factors (body mass index, smoking, alcohol intake) were measured for 2,002 Geneva, Switzerland, adults during 1999-2008 (two measurements, median 6 years apart), and 20 SNPs in 13 BL metabolism-related genes. Fixed and mixed effects repeated measures linear regression models, respectively, were employed to identify cross-sectional and longitudinal SNP:BL associations among the 1,516 (76%) study participants who reported not being treated for hypercholesterolemia at either measurement time. One-third more (12 vs. 9) longitudinal than cross-sectional associations were found [Bonferroni-adjusted two-tailed p < 0.00125 (=0.05/2)/20) for each of the four ensembles of 20 SNP:individual BL associations tested under the two study designs]. There was moderate consistency between the cross-sectional and longitudinal findings, with eight SNP:BL associations consistently identified across both study designs: [APOE.2 and APOE.4 (rs7412 and rs429358)]:TC; HL/LIPC (rs2070895):HDL; [APOB (rs1367117), APOE.2 and APOE.4 (rs7412 and rs429358)]:LDL; [APOA5 (rs2072560) and APOC III (rs5128)]:TG. The results suggest that cross-sectional studies, which include most genome-wide association studies (GWAS), can assess the large majority of SNP:BL associations. In the present analysis, which was much less powered than a GWAS, the cross-sectional study was around 2/3 (67%) as efficient as the longitudinal study. Show less

The APOA5 -1131 T/C polymorphism (rs662799) exhibits a very strong association with elevated TG levels in different racial groups. High resolution melting (HRM) analysis with the use of unlabeled probes has shown to be a convenient and reliable tool to genotyping, but not yet been used for detecting rs662799 polymorphism. We applied the unlabeled probe HRM analysis and direct DNA sequencing to assay the -1131T>C SNP in 130 cases DNA samples blindly. This HRM analysis can be completed in <3 min for each sample. The two melting peaks were displayed at 66.1±0.4°C for CC homozygote and 68.7±0.2°C for TT homozygote; TC heterozygote showed the both melting peaks. The genotyping results by HRM method were completely concordant with direct DNA sequencing. The distribution of CC, TC, and TT genotypes for the -1131T>C SNP was 9.2, 49.2, and 41.5%, respectively. This assay was sensitive enough to detect C allele down to 20% and 10% for T allele. The limit of detection for C and T allele was 6.2 and 2.5 ng/μL DNA, respectively. The developed unlabeled probe HRM method provides an alternative mean to detect ApoA5 -1131T>C SNP rapidly and accurately. Show less

Type 2 diabetes mellitus is a metabolic, vascular, and neuropathic disease with a high risk of atherosclerotic events due to dyslipidemic states. Polymorphisms in Apolipoprotein A5 gene (APOA5) have been associated with increased triglyceride levels in many different populations. This study aimed to identify the frequencies of the APOA5 -1131T>C and SW19 polymorphisms and evaluate their effects on lipid levels in patients with type 2 diabetes. Genotyping of APOA5 -1131T>C and SW19 polymorphisms was performed by PCR-RFLP in 146 diabetic patients and in controls (n = 173), from 30 to 80 years of age. Diabetic patients were divided into two groups: patients not treated with lipid lowering drugs (group G1; n = 62) and those treated with lipid lowering drugs (group G2, n = 84). Lipids and lipoproteins were determined enzymatically. Among participants not treated with lipid-lowering drugs (diabetics G1 and controls; n = 235), the -1131C was associated with lower LDLc levels (p = 0.015). In the diabetic patients, the 19W allele was associated with higher triglyceride levels (p = 0.004). In G1 diabetic patients, the combined analysis of APOA5 -1131T>C and SW19 polymorphisms showed that [TC or CC] + SS carriers presented lower total cholesterol levels than did other genotype combinations (p = 0.049). It could therefore be concluded that APOA5 -1131T>C and SW19 polymorphisms influence lipid levels in type 2 diabetic patients. Show less

The discovery of apolipoprotein A-V (apoA-V) in 2001 has raised a number of intriguing questions about its role in lipid transport and triglyceride (TG) homeostasis. Genome wide association studies (GWAS) have consistently identified APOA5 as a contributor to plasma TG levels. Single nucleotide polymorphisms (SNP) within the APOA5 gene locus have been shown to correlate with elevated plasma TG. Furthermore, transgenic and knockout mouse models support the view that apoA-V plays a critical role in maintenance of plasma TG levels. The present review describes recent concepts pertaining to apoA-V SNP analysis and their association with elevated plasma TG. The interaction of apoA-V with glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) is discussed relative to its postulated role in TG-rich lipoprotein catabolism. The potential role of intracellular apoA-V in regulation of TG homeostasis, as a function of its ability to associate with cytosolic lipid droplets, is reviewed. While some answers are emerging, numerous mysteries remain with regard to this low abundance, yet potent, modulator of TG homeostasis. Given the strong correlation between elevated plasma TG and heart disease, there is great scientific and public interest in deciphering the numerous biological riddles presented by apoA-V. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease. Show less

Triglyceride (TG) is a complex phenotype influenced by both genetic and environmental factors. Recent genome-wide association studies (GWAS) have identified genes or loci affecting lipid levels; however, such studies in Chinese populations are limited. A two-stage GWAS were conducted to identify genetic variants that were associated with TG in a Chinese population of 3495 men. Gene-environment interactions on serum TG levels were further investigated for the seven single nucleotide polymorphisms (SNPs) that were studied in both stages. Two previously reported SNPs (rs651821 in APOA5, rs328 in LPL) were replicated in the second stage, and the combined P-values were 9.19 × 10(-26) and 1.41 × 10(-9) for rs651821 and rs328, respectively. More importantly, a significant interaction between aldehyde dehydrogenase 2 (ALDH2) rs671 and alcohol consumption on serum TG levels were observed (P = 3.34 × 10(-5)). Rs671 was significantly associated with serum TG levels in drinkers (P = 1.90 × 10(-10)), while no association was observed in non-drinkers (P > 0.05). For drinkers, men carrying the AA/AG genotype have significantly lower serum TG levels, compared with men carrying the GG genotype. For men with the GG genotype, the serum TG levels increased with the quantity of alcohol intake (P = 1.28 × 10(-8) for trend test). We identified a novel, significant interaction effect between alcohol consumption and the ALDH2 rs671 polymorphism on TG levels, which suggests that the effect of alcohol intake on TG occurs in a two-faceted manner. Just one drink can increase TG level in susceptible individuals who carry the GG genotype, while individuals carrying AA/AG genotypes may actually benefit from moderate drinking. Show less

We previously demonstrated in streptozotocin-induced diabetic mice that deficiency or inhibition of aldose reductase (AR) caused significant dephosphorylation of hepatic transcriptional factor PPARα, leading to its activation and significant reductions in serum lipid levels. Herein, we report that inhibition of AR by zopolrestat or by a short-hairpin RNA (shRNA) against AR caused a significant reduction in serum and hepatic triglycerides levels in 10-week old diabetic db/db mice. Meanwhile, hyperglycemia-induced phosphorylation of hepatic ERK1/2 and PPARα was significantly attenuated in db/db mice treated with zopolrestat or AR shRNA. Further, in comparison with the untreated db/db mice, the hepatic mRNA expression of Aco and ApoA5, two target genes for PPARα, was increased by 93% (P < 0.05) and 73% (P < 0.05) in zopolrestat-treated mice, respectively. Together, these data indicate that inhibition of AR might lead to significant amelioration in hyperglycemia-induced dyslipidemia and nonalcoholic fatty liver disease. Show less

The effects of red clover extract and its bioactive components, biochanin A and formononetin, on the blood glucose and lipid levels of streptozotocin (STZ) induced-diabetic mice were investigated. Male diabetic C57BL/6 mice were induced by multiple low-dose STZ administration and then treated with red clover extract or isoflavones for a period of 3 weeks. Red clover extract had no significant effect on lowering the blood glucose levels of STZ-diabetic mice. Similarly, biochanin A and formononetin exerted no hypoglycemic effect. However, the serum triglycerides, total cholesterols and low-density lipoprotein-cholesterol levels for STZ-diabetic mice receiving red clover extract were significantly lower than that of untreated STZ-diabetic mice. In addition, treatment with biochanin A or formononetin significantly ameliorated these lipid profiles in diabetic mice. The mRNA expression of two target genes transcriptionally regulated by peroxisome proliferator-activated receptor (PPAR) α were determined by semi-quantitative RT-PCR and biochanin A or formononetin were found to significantly down-regulate hepatic APOC3 expression, whereas they had no significant effect on hepatic APOA5 expression. Thus we conclude that red clover extract and biochanin A or formononetin significantly ameliorate the lipid profiles of STZ-diabetic mice and these effects are achieved at least in part by activating hepatic PPARα. Show less

Apolipoprotein A5 (APOA5) was identified as a strong modulator of serum lipids. Moreover, an APOA5 gene -1131T>C polymorphism has been associated with serum lipids, but the results are inconsistent according to ethnic and racial groups. We have genotyped and analyzed 1,619 outpatients of Korean oriental medicine hospitals who were classified into three Sasang constitution groups (SCGs), So-Yang (SY), So-Eum (SE), and Tae-Eum (TE). There were no significant difference in the distribution of the APOA5 -1131T>C genotype among the three SCGs. Subjects with the C allele in SY and TE showed significantly lower serum high-density lipoprotein cholesterol (HDL-C) and higher triglyceride (TG) levels than noncarriers of the C allele. These results show the differences in the prevalence of decreasing serum HDL-C and elevating serum TG levels along with APOA5 -1131T>C polymorphism according to SCG and suggest that SCG may act as a significant risk factor for hypo-HDL-C-emia and hypertriglyceridemia susceptibility. Show less

The genetic underpinnings of both normal and pathological variation in plasma triglyceride (TG) concentration are relatively well understood compared to many other complex metabolic traits. For instance, genome-wide association studies (GWAS) have revealed 32 common variants that are associated with plasma TG concentrations in healthy epidemiologic populations. Furthermore, GWAS in clinically ascertained hypertriglyceridemia (HTG) patients have shown that almost all of the same TG-raising alleles from epidemiologic samples are also associated with HTG disease status, and that greater accumulation of these alleles reflects the severity of the HTG phenotype. Finally, comprehensive resequencing studies show a burden of rare variants in some of these same genes - namely in LPL, GCKR, APOB and APOA5 - in HTG patients compared to normolipidemic controls. A more complete understanding of the genes and genetic variants associated with plasma TG concentration will enrich our understanding of the molecular pathways that modulate plasma TG metabolism, which may translate into clinical benefit. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease. Show less

Apolipoprotein A5 (APOA5) over-expression enhances lipolysis of triglyceride (TG) through stimulation of lipoprotein lipase (LPL) activity; however, an APOA5 G185C variant was found associated with hypertriglyceridemia. The aim of this study was, therefore, to explore the importance of APOA5 185GG in the activation of LPL. A fragment containing mature human APOA5 cDNA was obtained by RT-PCR and subcloned into pET-15b vector. Site-directed mutagenesis was performed to generate 19 variants. Recombinant human APOA5 wild type and variants were produced in Escherichia coli, and then activation of LPL was measured. Activity of APOA5 variants on LPL-mediated 1,2-dimyristoyl-sn-glycero-3-phosphocholine hydrolysis was reduced by 17 to 74% in comparison to wild type APOA5 (P<0.0001). All variants also showed reduced activation (P<0.0001) of LPL-mediated hydrolysis of very low-density lipoprotein (VLDL); activation abilities of APOA5 variants ranged from 31 to 81% of wild-type APOA5. APOA5 residue 185G is very important in LPL-mediated VLDL hydrolysis, and any mutation at this residue will decrease LPL activation and concomitant TG modulation. Show less

Preoperative portal vein embolization (PVE) is used to increase the future remnant liver (FRL) in patients requiring extensive liver resection. Computed tomography (CT) volumetry, performed not earlier than 3-6 weeks after PVE, is commonly employed to assess hypertrophy of the FRL following PVE. Early parameters to predict effective hypertrophy are therefore desirable. The aim of the present study was to assess plasma bile salt levels, triglycerides (TG), and apoA-V in the prediction of the hypertrophy response during liver regeneration. Serum bile salt, TG, and apoA-V levels were determined in 20 patients with colorectal metastases before PVE, and 5 h, 1, and 21 days after PVE, as well as prior to and after (day 1-7, and day 21) subsequent liver resection. These parameters were correlated with liver volume as measured by CT volumetry (%FRL-V), and liver function was determined by technetium-labeled mebrofenin hepatobiliary scintigraphy using single photon emission computed tomography. Triglyceride levels at baseline correlate with volume increase of the future remnant liver (FRL-V) post-PVE. Also, bile salts and TG 5 h after PVE positively correlated with the increase in FRL volume (r=0.672, p=0.024; r=0.620, p=0.042, resp.) and liver function after 3 weeks (for bile salts r=0.640, p=0.046). Following liver surgery, TG levels at 5 h and 1 day after resection were associated with liver remnant volume after 3 months (r=0.921, p=0.026 and r=0.981, p=0.019, resp). Plasma apoA-V was increased during liver regeneration. Bile salt and TG levels at 5 h after PVE/resection are significant early predictors of liver volume and functional increase. It is suggested that these parameters can be used for early timing of volume assessment and resection after PVE. Show less

The common functional variants of the apolipoprotein A5 (APOA5) and the glucokinase regulatory protein genes (GCKR) have been shown to associate with increased fasting triglyceride (TG) levels. Albeit the basic association has been extensively investigated in several populations of different origin, less is known about quantitative traits of them. In our study accumulation rates of four APOA5 (T-1131, IVS3 + G476A, T1259C and C56G) and two GCKR (C1337T and rs780094) functional SNPs were analyzed in patients stratified into four TG quartile groups. Randomly selected 325 metabolic syndrome patients were separated into four quartile (q) groups based on the TG levels as follows q1: TG <1.38 mmol/l; q2: 1.38-1.93 mmol/l; q3: 1.94-2.83 mmol/l; and q4: TG >2.83 mmol/l. We observed significant stepwise increase of prevalence rates of minor allele frequencies in the four plasma TG quartiles for three APOA5 SNPs: -1131C (q1: 4.94%; q2: 8.64%; q3: 11.6%; q4: 12.3%), IVS3 + 476A (q1: 4.32%; q2: 7.4%; q3: 10.36%; q4: 11.1%), and 1259C (q1: 4.94%; q2: 7.41%; q3: 10.4%; q4: 11.7%). The haplotype analysis revealed, that the frequency of APOA5*2 haplotype gradually increased in q2, q3 and q4 (q1: 9.87%; q2: 14.8%; q3: 18.3%; q4: 21%). The distribution of the homozygotes of the two analyzed GCKR variants resembled to the APOA5 pattern. Contrary to the hypothetically predictable linear association coming from the current knowledge about the APOA5 and GCKR functions, the findings presented here revealed a unique, TG raise dependent gradual accumulation of the functional variants of in MS patients. Thus, the findings of the current study serve indirect evidence for the existence of rare APOA5 and GCKR haplotypes in metabolic syndrome patients with higher TG levels, which contribute to the complex lipid metabolism alteration in this disease. Show less

APOA5, a key gene regulating triglyceride (TG) levels, is reported to be expressed exclusively in the liver where it may regulate TG-rich particle synthesis and secretion. Since the same lipoprotein processing occurs in the intestine, we have postulated that this organ would also express APOA5. We have detected the APOA5 gene expression in C57BL/6J mouse and in human small intestine samples. In humans, it is expressed mainly in the duodenum and colon, with messenger RNA (mRNA) levels four orders of magnitude lower than in the liver, and the protein product being one-sixth of the liver equivalent. Subsequently, we carried out in vitro experiments in TC-7/CaCo(2) human intestinal cells to analyse the expression of APOA5, APOC3, APOB and MTP genes after the incubation with long- and short-chain fatty acids, and a peroxisome proliferator-activated receptor alpha (PPARα) agonist (Wy 14643, a fibrate therapeutic agent). In the TC-7 cell line, APOA5 expression was significantly upregulated by saturated fatty acids. The short-chain fatty acid butyrate increased APOA5 expression almost fourfold while APOB was downregulated by increasing butyrate concentrations. When TC-7 cells were incubated with PPARα agonist, the APOA5 expression was increased by 60%, while the expression of APOB, MTP and APOC3 was decreased by 50%, 30% and 45%, respectively. Our results demonstrate that APOA5 is expressed in the intestine, albeit at a much lower concentration than in the liver. While it remains to be determined whether intestinal apo A-V is functional, our in vitro experiments show that its expression is modifiable by dietary and pharmacological stimuli. Show less

Schizophrenic patients treated with clozapine or olanzapine often develop hypertriglyceridemia. The apolipoprotein A5 gene (APOA5), which affects VLDL production and lipolysis, has been implicated in the triglyceride (TG) metabolism. This study examined the association of common APOA5 genetic variants and TG levels in chronically institutionalized schizophrenic patients, on a stable dose of atypical antipsychotic (clozapine, olanzapine or risperidone. The TG levels in 466 schizophrenic patients treated with clozapine (n = 182), olanzapine (n = 89) or risperidone (n = 195) were measured. Patients were genotyped for the three APOA5 single nucleotide polymorphisms (SNPs) rs662799 (-1131T > C), rs651821 (3A > G) and rs2266788 (1891T > C). A gene × drug interaction with TG levels was observed. In single-marker-based analysis, the minor alleles of the two polymorphisms (-1131C and -3G) were observed to be associated with increased TGs in patients treated with risperidone, but not with clozapine or olanzapine. Haplotype analysis further revealed that carriers of the haplotype constructed with the three minor alleles had higher TG levels than those who did not carry this haplotype in patients taking risperidone (CGC((+/+)) vs. = 125.4 ± 59.1 vs. 82.2 ± 65.8, P = 0.015; CGC((-/+ )) vs. CGC((-/-)) = 113.7 ± 80.4 vs. 82.2 ± 65.8, P = 0.012). Our findings extend and add new information to the existing data regarding the association between APOA5 and TG regulation during long-term atypical antipsychotic treatment. Show less

Accumulating evidence suggests that elevated plasma triglycerides concentrations, in both the fasting and the postprandial states, may pose a significant independent risk for cardiovascular disease (CVD). Both fasting and postprandial lipoprotein concentrations vary substantially among individuals, and this inter individual variability is driven by a combination of non-genetic and genetic factors. Regarding the genetic component, the efforts to elucidate the variability in postprandial response have resulted in the identification of associations with multiple lipid candidate genes. However, most reported associations are based on very simple models including one single-nucleotide polymorphism (SNP) or haplotype at a time and small sample sizes. Progress in this promising area of research requires more comprehensive experimental models, including larger sample sizes that will allow investigating gene-gene interactions. Reviews of the literature in the area of ApoA5, GCKR, and PLIN genes and postprandial lipemia are used to demonstrate the complexities of genotype-phenotype associations. Knowledge of how these and other genes influence postprandial response should increase the understanding of personalised nutrition. Show less

To investigate the association of the -12238T/C polymorphism of apolipoprotein A5 (APOA5) gene with coronary heart disease (CHD) and the influence of serum lipid levels in Chinese Uygur population of Xinjiang. The -12238T/C polymorphism of APOA5 gene in 344 patients with CHD and 408 controls was analyzed by polymerase chain reaction-restriction fragment length polymorphism; the serum lipid levels were detected as well. The frequencies of CC, TC and TT genotype were 6.69%, 43.31% and 50.00% in the CHD group, while they were 14.95%, 45.10% and 39.95% in the control group. There was significant difference in the distribution of genotypes between the two groups (P < 0.01). Logistic regression analyses adjusted for age, gender, smoking, serum total cholesterol, presence of hypertension and diabetes revealed that individuals carrying CC genotype had an increased risk of CHD compared with TT genotype (OR = 0.328, 95%CI: 0.154-0.700). There was also significant difference in serum triglyceride level in genotypes between these two groups (P < 0.01). Patients in CHD group who carried CC and TC genotypes had lower serum triglyceride level than the TT genotype carriers. The -12238T/C polymorphism of APOA5 gene has influence on the serum triglyceride level in Uygur population of Xinjianxg. This polymorphism might be associated with development of CHD, and the CC genotype might be a protective factor in the development of CHD. Show less

Genomewide association studies (GWAS), conventional association studies and the characterization of families with ApoA5 deficiency have shown that variation in the apolipoprotein A5 (APOA5) gene is associated with plasma triglyceride levels. The aim of this study was to determine the frequency of rare variants in the APOA5 gene in patients with various forms of hypertriglyceridemia. The DNA sequence of the exons plus exon/intron boundaries of the APOA5 gene of 291 patients with triglycerides above the 95th percentile for age and sex (98 of whom had triglycerides above 875 mg/dl), 111 patients with APOE2/2 genotype of whom 100 had Type III Hyperlipidemia and 108 probands with triglycerides below the 25th percentile for age and sex was determined. Twenty four variants were detected of which eight have been previously reported. There were nine patients with triglycerides above 875 mg/dl and nine patients with moderately elevated triglycerides who were carriers of at least one deleterious mutation in the APOA5 gene. Of the patients with Type III HLP, three (3%) were carriers of rare variants and there was a single rare variant detected in the group of probands with triglycerides below the 25th percentile for age and sex. Rare mutations in the APOA5 gene are more frequent in patients with elevated triglycerides than in those with Type III HLP. Show less

Atherosclerosis is the major cause of coronary artery disease (CAD), and oxidized LDL (oxLDL) is believed to play a key role in the initiation of the atherosclerotic process. Recent studies show that inflammation and autoimmune reactions are also relevant in atherosclerosis. In this study, we examined the association of antibodies against oxLDL (anti-oxLDL) with the severity of CAD in 558 Women's Ischemia Syndrome Evaluation (WISE) study samples (465 whites; 93 blacks) determined by coronary stenosis (< 20%, 20%-49%, > 50% stenosis). We also examined the relationship of anti-oxLDL with serum lipid levels and nine candidate genes including APOE, APOH, APOA5, LPL, LRP1, HL, CETP, PON1, and OLR1. IgM anti-oxLDL levels were significantly higher in the >20% stenosis group than in the ≥ 20% stenosis group in whites (0.69 ± 0.02 vs. 0.64 ± 0.01, respectively; P = 0.02). IgM anti-oxLDL levels correlated significantly with total cholesterol (r² = 0.01; P = 0.03) and LDL cholesterol (r² = 0.017; P = 0.004) in whites. Multiple regression analysis revealed a suggestive association of LPL/S447X single-nucleotide polymorphism (SNP) with both IgG anti-oxLDL (P = 0.02) and IgM anti-oxLDL (P = 0.07), as well as between IgM anti-oxLDL and the OLR1/3'UTR SNP (P = 0.020). Our data suggest that higher IgM anti-oxLDL levels may provide protection against coronary stenosis and that genetic variation in some candidate genes are determinants of anti-oxLDL levels. Show less