<Emphasis Type="Italic">ABCA1</Emphasis> gene polymorphisms and their associations with coronary artery disease and plasma lipids in males from three ethnic populations in Singapore

Mutations in the ATP-binding cassette transporter ABCA1 underlie Tangier disease and familial hypoalphaliproteinemia (FHA), disorders that are characterised by reduced high-density lipoprotein-cholesterol (HDL-C) concentration and cholesterol efflux, and increased coronary artery disease (CAD). We explored if polymorphisms in the ABCA1 gene are associated with CAD and variations in plasma lipid levels, especially HDL-C, and whether the associations may depend on ethnicity. Male cases and controls from the Singapore Chinese, Malay and Indian populations were genotyped for five ABCA1 single nucleotide polymorphisms. Various single-locus frequency distribution differences between cases and controls were detected in different ethnic groups: the promoter -14C>T in Indians, exon 18 M883I in Malays, and 3'-untranslated (UTR) region 8994A>G in Chinese. For the Malay population, certain haplotypes carrying the I825- A (exon 17) and M883- G alleles were more frequent among cases than controls, whereas the converse was true for the alternative configuration of V825- G and I883- A, and this association was reinforced in multi-locus disequilibrium analysis that utilized genotypic data. In the healthy controls, associations were found for -14C>T genotypes with HDL-C in Chinese; 237indelG (5'UTR) with apolipoprotein A1 (apoA1) in Malays and total cholesterol (TC) in Indians; M883I with lipoprotein(a) [Lp(a)] in Malays and apolipoprotein B (apoB) in Chinese; and 8994A>G with Lp(a) in Malays, and TC, low-density lipoprotein-cholesterol (LDL-C) as well as apoB in Indians. While genotype-phenotype associations were not reproduced across populations and loci, V825I and M883I were clearly associated with CAD status in Malays with no effects on HDL-C or apoA1.     

甲亢患者甲状腺激素水平与血脂代谢相关性分析及临床意义探讨

目的:探讨甲亢患者甲状腺激素水平与血脂代谢指标之间的关系。方法:对160例甲亢患者治疗前后的甲状腺激素(TH)水平、血脂水平进行对照分析。结果:甲亢治疗前后与健康对照组比较,游离三碘甲状腺原氨酸(FT3)、游离甲状腺素(FT4)明显增高,促甲状腺激素(TSH)明显降低,差异有统计学意义(P<0.01);总胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白胆固醇(LDL-C)、载脂蛋白A(apoAΙ)、载脂蛋白B(apoB)均明显降低,且差异具有统计学意义(P<0.01);低密度脂蛋白胆固醇(HDL-C)无明显变化(P>0.05)。结论:甲状腺激素与脂类代谢密切相关,临床上在诊治甲亢患者时,应当加强血脂水平的监测,以便更好地指导临床诊治,为疾病的发生发展、判断预后提供有价值的实验室检测指标。     

Lipid Absorption Defects in Intestine-specific Microsomal Triglyceride Transfer Protein and ATP-binding Cassette Transporter A1-deficient Mice

We have previously described apolipoprotein B (apoB)-dependent and -independent cholesterol absorption pathways and the role of microsomal triglyceride transfer protein (MTP) and ATP-binding cassette transporter A1 (ABCA1) in these pathways. To assess the contribution of these pathways to cholesterol absorption and to determine whether there are other pathways, we generated mice that lack MTP and ABCA1, individually and in combination, in the intestine. Intestinal deletions of Mttp and Abca1 decreased plasma cholesterol concentrations by 45 and 24%, respectively, whereas their combined deletion reduced it by 59%. Acute cholesterol absorption was reduced by 28% in the absence of ABCA1, and it was reduced by 92–95% when MTP was deleted in the intestine alone or together with ABCA1. MTP deficiency significantly reduced triglyceride absorption, although ABCA1 deficiency had no effect. ABCA1 deficiency did not affect cellular lipids, but Mttp deficiency significantly increased intestinal levels of triglycerides and free fatty acids. Accumulation of intestinal free fatty acids, but not triglycerides, in Mttp-deficient intestines was prevented when mice were also deficient in intestinal ABCA1. Combined deficiency of these genes increased intestinal fatty acid oxidation as a consequence of increased expression of peroxisome proliferator-activated receptor-γ (PPARγ) and carnitine palmitoyltransferase 1α (CPT1α). These studies show that intestinal MTP and ABCA1 are critical for lipid absorption and are the main determinants of plasma and intestinal lipid levels. Reducing their activities might lower plasma lipid concentrations.     

脂代谢相关基因在apoE基因缺失幼龄小鼠肝脏中的表达

本文旨在分析脂代谢相关基因在载脂蛋白E(apolipoprotein E,apoE)基因缺失(apoE-/-)幼龄小鼠肝脏中的表达特征及其与血脂紊乱和动脉粥样硬化(atherosclerosis,AS)早期病变的关系.利用半定量RT-PCR和荧光实时定量RT-PCR技术,分析14 d龄、1、2和3月龄apoE-/-小鼠及同龄野生型(wild type,WT)小鼠肝脏脂代谢相关基因的表达,并进行血生化指标及主动脉病理形态学榆测.apo-/-小鼠肝脏中apoAI、apoAIV表达在14d龄时即发生显著变化(P<0.05);在1月龄时apoB10G表达较同龄WT小鼠明显上调(P＜0.05);apoA V表达则在2月龄时较同龄WT小鼠上调(P＜0.05),此时可观察到apoE-/-小鼠主动脉内膜出现AS早期病变;Faf/CD36和Angptl 3表达在3月龄时较同龄WT小鼠上调(P＜0.05);实验中检测的其它基因的mRNA表达与同龄WT小鼠相比无显著性差异.apoE-/-小鼠血清总胆同醇、甘油三酯、低密度脂蛋白胆固醇和高密度脂蛋白胆固醇含量均高于同龄WT小鼠,并随年龄增长而升高.apoE-/-小鼠和同龄WT小鼠血清中apoB100蛋白浓度在14 d龄到3月龄问变化趋势与其在肝脏中mRNA表达及血清中低密度脂蛋白胆崮醇含量变化趋势基本一致.上述部分脂代谢相关基因表达在幼龄小鼠即发生改变,与血脂紊乱以及主动脉AS病变发生发展过程呈正相关,说明其可能在幼龄小鼠脂质代谢紊乱发生过程中起重要作用,从而引起动脉内皮细胞功能改变乃至AS早期病变的发生.     

高糖低脂膳食对健康大学生血清apoAⅠ和apoB100水平及apoAⅠ/apoB100的影响

高脂血症是典型的多因素、多基因疾病.为探讨青年人性别、体质指数(BMI)与高糖低脂膳食之间的相互作用及其与血清脂质、载脂蛋白apoAⅠ,apoB100及apoAⅠ/apoB100的关系,本研究招募了27名男性（22.96±1.95岁）及29名女性（22.83±1.67岁）健康大学生志愿者,给予7 d平衡膳食和6 d高糖低脂膳食,分别在第1 d,第8 d及第14 d晨取空腹血,测定血清甘油三脂（TG）、总胆固醇（TC）、葡萄糖（Glu）、高密度脂蛋白胆固醇（HDL-C）、非低密度脂蛋白胆固醇（NLDL-C）、apoAⅠ及apoB100,计算低密度脂蛋白胆固醇（LDL-C）含量和apoAⅠ/apoB100比值.组分分析发现,高糖低脂膳食后,TG、HDL-C显著升高(P ＜0.01）,TC、LDL-C显著降低（P <0001）.同时,apoAⅠ及apoAⅠ/apoB100显著增加（P ＜0.05）,apoB100没有明显变化.性别分组分析发现,高糖低脂膳食后,男性apoAⅠ/apoB100显著增加（P ＜0.05）,apoAⅠ、apoB100没有显著改变;女性apoAⅠ、apoB100、apoAⅠ/apoB100均无显著变化.BMI分组分析发现,在14≤BMI＜19、19≤BMI＜23和23≤BMI＜29三组中,仅14≤BMI＜19组apoAⅠ（P <0.05）及apoAⅠ/apoB100（P ＜0.01）显著升高.但男性14≤BMI＜19组和23≤BMI＜29组apoAⅠ显著增加（P <0.05）,19≤BMI＜23组apoB100则显著降低（P ＜0.05）,apoAⅠ/apoB100在14≤BMI＜19组和19≤BMI＜23组显著增加（P ＜0.01）.而女性仅在14≤BMI＜19组apoAⅠ/apoB100显著增高（P ＜0.05）.结果表明,在健康大学生中,性别、BMI、高糖低脂膳食之间的相互作用在高糖诱导的高甘油三酯血症血清apoAⅠ,apoB100及apoAⅠ/apoB100的改变中起着重要的作用.     

The ATP-binding cassette transporter 1 mediates lipid efflux from Sertoli cells and influences male fertility

The liver X receptor/retinoid X receptor (LXR/RXR)-regulated gene ABCA1 effluxes cellular cholesterol and phospholipid to apolipoprotein A1 (apoA1), which is the rate-limiting step in high-density lipoprotein synthesis. The RXR pathway plays a critical role in testicular lipid trafficking, and RXRbeta-deficient male mice are sterile and accumulate lipids in Sertoli cells. Here, we demonstrate that ABCA1 mRNA and protein are abundant in Sertoli cells, whereas germ cells express little ABCA1. LXR/RXR agonists stimulate ABCA1 expression in cultured Sertoli MSC1 and Leydig TM3 cell lines. However, Sertoli TM4 cells lack ABCA1, and TM4 cells or primary Sertoli cells cultured from ABCA1(-/-) mice both fail to efflux cholesterol to apoA1. Expression of exogenous ABCA1 restores apoA1-dependent cholesterol efflux in Sertoli TM4 cells. In vivo, ABCA1-deficient mice exhibit lipid accumulation in Sertoli cells and depletion of normal lipid droplets from Leydig cells by 2 months of age. By 6 months of age, intratesticular testosterone levels and sperm counts are significantly reduced in ABCA1(-/-) mice compared with wild-type (WT) controls. Finally, a 21% decrease (P = 0.01) in fertility was observed between ABCA1(-/-) males compared with WT controls across their reproductive lifespans. These results show that ABCA1 plays an important role in lipid transport in Sertoli cells and influences male fertility.     

军事飞行员血浆脂蛋白与同型半胱氨酸水平及其相关性分析

目的:分析某部军事飞行员血浆脂蛋白和同型半胱氨酸水平及其相关性。方法:比较某部军事飞行员与地勤人员总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDLC)、低密度脂蛋白胆固醇(LDLC)、载脂蛋白A1(apoA1)、载脂蛋白B(apoB)、同型半胱氨酸(Hcy)血清水平,并分析Hcy与TC、TG、HDLC、LDLC、apoA1、apoB等的相关性。结果:多元线性回归分析飞行员组的Hcy与HDLC值正相关(t=2.42,Sig=0.017),与apoA1值负相关(t=-2.49,Sig=0.014);飞行员与地勤人员的LDLC、apoB、apoA1水平差异有统计学意义(P0.05);高Hcy飞行员组的HDLC、apoB、apoB/apoA1比正常Hcy飞行员组显著增高,差异有统计学意义(P0.05)。结论:军事飞行员常规体检增加Hcy、apoA1、apoB及其比值检测,对异常结果分析后进行早期干预和治疗,这对飞行员的健康维护和保障飞行安全具有现实意义。     

Association of polymorphisms at restriction enzyme recognition sites of apolipoprotein B and E gene with dyslipidemia in children undergoing primary nephrotic syndrome

Background Dyslipidemia, a common complication, is very prevalent in children with primary nephrotic syndrome (PNS). Recent studies have shown that genetic basis may be involved in the onset of HLP secondary to PNS. ApoB and E have been identified as the important candidate genes for lipid abnormalities. Objective: To investigate the association of apolipoprotein B (apoB) and E (apoE) genetic polymorphisms (Xba I, EcoR I, Msp I, and Hha I) with parameters describing the serum lipid profiles in children undergoing PNS. Methods: Genomic DNA was extracted from 250 children diagnosed with PNS and 200 healthy controls with neither allergic nor renal disease. ApoB (Xba I, EcoR I, and Msp I) and apoE (Hha I) genotypes were determined by PCR-restriction fragment length polymorphism (RFLP) analysis. The fasting serum lipoprotein (a) [Lp(a)], total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (apoA1), apoB, and total protein from a 24-h urine sample were measured. Results: No significant differences in genotypes and alleles frequencies were observed for the apoB Xba I, EcoR I, Msp I and the apoE Hha I restriction sites in PNS patients as compared to controls (P > 0.05). Patients and controls with X + allele exhibited significantly higher serum levels of Lp(a), TC, nonHDL-C, LDL-C, LDL-C/HDL-C ratio, and apoB than that with X− allele (P < 0.05), whereas for apoA1/B ratio the opposite was found (P < 0.01). E−/E− carriers had significantly higher Lp(a), TC, HDL-C, and apoA1 concentrations than did E+/E− or E+/E+ carriers in control group (P < 0.05). Healthy children carrying the rare EcoR I allele had higher mean Lp(a), TC, and HDL-C levels than homozygotes for E+ (P < 0.05). Higher Lp(a) serum concentrations were observed in patients with E− allele (P < 0.05). No significant differences in lipid parameters were determined for the apoB Msp I and apoE Hha I the polymorphisms study (P > 0.05). When genetic variations were compared with urinary protein excretion, the Xba I X− allele was more frequent in patients with elevated proteinuria (P < 0.01). Conclusion: Presence of Xba I X+ allele and/or EcoR I E− at the apoB gene may be risk factors for lipid abnormalities secondary to childhood PNS.     

Identification of the Flavonoid Luteolin as a Repressor of the Transcription Factor Hepatocyte Nuclear Factor 4α

Hepatocyte nuclear factor 4α (HNF4α) is a nuclear receptor that regulates the expression of genes involved in the secretion of apolipoprotein B (apoB)-containing lipoproteins and in glucose metabolism. In the present study, we identified a naturally occurring flavonoid, luteolin, as a repressor of HNF4α by screening for effectors of the human microsomal triglyceride transfer protein (MTP) promoter. Luciferase reporter gene assays revealed that the activity of the MTP gene promoter was suppressed by luteolin and that the mutation of HNF4α-binding element abolished luteolin responsiveness. Luteolin treatment caused a significant decrease in the mRNA levels of HNF4α target genes in HepG2 cells and inhibited apoB-containing lipoprotein secretion in HepG2 and differentiated Caco2 cells. The interaction between luteolin and HNF4α was demonstrated using absorption spectrum analysis and luteolin-immobilized beads. Luteolin did not affect the DNA binding of HNF4α to the promoter region of its target genes but suppressed the acetylation level of histone H3 in the promoter region of certain HNF4α target genes. Short term treatment of mice with luteolin significantly suppressed the expression of HNF4α target genes in the liver. In addition, long term treatment of mice with luteolin significantly suppressed their diet-induced obesity and improved their serum glucose and lipid parameters. Importantly, long term luteolin treatment lowered serum VLDL and LDL cholesterol and serum apoB protein levels, which was not accompanied by fat accumulation in the liver. These results suggest that the flavonoid luteolin ameliorates an atherogenic lipid profile in vivo that is likely to be mediated through the inactivation of HNF4α.     

Surface Tensiometry of Apolipoprotein B Domains at Lipid Interfaces Suggests a New Model for the Initial Steps in Triglyceride-rich Lipoprotein Assembly

Apolipoprotein B (apoB) is the principal protein component of triacylglyceride (TAG)-rich lipoproteins, including chylomicrons and very low density lipoprotein, which is the precursor to LDL (the “bad cholesterol”). TAG-rich lipoprotein assembly is initiated by the N-terminal βα1 superdomain of apoB, which co-translationally binds and remodels the luminal leaflet of the rough endoplasmic reticulum. The βα1 superdomain contains four domains and is predicted to interact directly with lipids. Using drop tensiometry, we examined the interfacial properties of the α-helical and C-sheet domains and several subdomains to establish a detailed structure-function relationship at the lipid/water interface. The adsorption, stress response, exchangeability, and pressure (Π)-area relationship were studied at both triolein/water and triolein/1-palmitoyl, 2-oleoylphosphatidylcholine/water interfaces that mimic physiological environments. The α-helical domain spontaneously adsorbed to a triolein/water interface and formed a viscoelastic surface. It was anchored to the surface by helix 6, and the other helices were ejected and/or remodeled on the surface as a function of surface pressure. The C-sheet instead formed an elastic film on a triolein/water interface and was irreversibly anchored to the lipid surface, which is consistent with the behavior of amphipathic β-strands. When both domains were adsorbed together on the surface, the C-sheet shielded a portion of the α-helical domain from the surface, which retained its globular structure. Overall, the unique secondary and tertiary structures of the N-terminal domains of apoB support the intrinsic capability of co-translational lipid recruitment. The evidence presented here allows the construction of a detailed model of the initiation of TAG-rich lipoprotein assembly.     

Lipoprotein (a) upregulates ABCA1 in liver cells via scavenger receptor-B1 through its oxidized phospholipids

Elevated levels of lipoprotein (a) [Lp(a)] are a well-established risk factor for developing CVD. While Lp(a) levels are thought to be independent of other plasma lipoproteins, some trials have reported a positive association between Lp(a) and HDL. Whether Lp(a) has a direct effect on HDL is not known. Here we investigated to determine whether Lp(a) had any effect on the ABCA1 pathway of HDL production in liver cells. Incubation of HepG2 cells with Lp(a) upregulated the PPARγ protein by 1.7-fold and the liver X receptor α protein by 3-fold. This was accompanied by a 1.8-fold increase in ABCA1 protein and a 1.5-fold increase in cholesterol efflux onto apoA1. We showed that Lp(a) was internalized by HepG2 cells, however, the ABCA1 response to Lp(a) was mediated by the selective uptake of oxidized phospholipids (oxPLs) from Lp(a) via the scavenger receptor-B1 and not by Lp(a) internalization per se. We conclude that there is a biological connection between Lp(a) and HDL through the ability of Lp(a)’s oxPLs to upregulate HDL biosynthesis.     

CTRP12 ameliorates atherosclerosis by promoting cholesterol efflux and inhibiting inflammatory response via the miR-155-5p/LXRα pathway

C1q tumor necrosis factor-related protein 12 (CTRP12), a conserved paralog of adiponectin, is closely associated with cardiovascular disease. However, little is known about its role in atherogenesis. The aim of this study was to examine the influence of CTRP12 on atherosclerosis and explore the underlying mechanisms. Our results showed that lentivirus-mediated CTRP12 overexpression inhibited lipid accumulation and inflammatory response in lipid-laden macrophages. Mechanistically, CTRP12 decreased miR-155-5p levels and then increased its target gene liver X receptor α (LXRα) expression, which increased ATP binding cassette transporter A1 (ABCA1)- and ABCG1-dependent cholesterol efflux and promoted macrophage polarization to the M2 phenotype. Injection of lentiviral vector expressing CTRP12 decreased atherosclerotic lesion area, elevated plasma high-density lipoprotein cholesterol levels, promoted reverse cholesterol transport (RCT), and alleviated inflammatory response in apolipoprotein E-deficient (apoE^−/−) mice fed a Western diet. Similar to the findings of in vitro experiments, CTRP12 overexpression diminished miR-155-5p levels but increased LXRα, ABCA1, and ABCG1 expression in the aortas of apoE^−/− mice. Taken together, these results suggest that CTRP12 protects against atherosclerosis by enhancing RCT efficiency and mitigating vascular inflammation via the miR-155-5p/LXRα pathway. Stimulating CTRP12 production could be a novel approach for reducing atherosclerosis.Subject terms: Non-coding RNAs, Cardiovascular diseases     

Association of TNF-α polymorphisms (−857, −863 and −1031), TNF-α serum level and lipid profile with acne vulgaris

BackgroundAcne is an inflammatory condition principally affected by genetic and dietary factors. Investigation into functional polymorphisms of TNF-α gene and their association with acne vulgaris will be helpful in exploring genetic influence on skin immune mediated inflammatory events. In the present study, we analyzed association of TNF-α gene polymorphisms, its expression levels and lipid profiles in a large cohort of acne patients and controls.MethodsWe used PCR-RFLP to study association of TNF-α polymorphisms at −857C/T, −863C/A and −1031 T/C sites with acne vulgaris. Lipid profiles were measured using enzymatic end-point method. The serum levels of TNF-α and apolipoprotein a were measured using ELISA. NIH, LDlink was used to investigate patterns of linkage disequilibrium across south Asian reference genome (Punjabi from Lahore Pakistan).ResultsWe found that TNF-α −863 polymorphism is strongly associated with acne in overall population as well as in gender and severity based groups of acne patients. Polymorphisms at −863 and −1031 position were in linkage disequilibrium. Importantly, TNF-α serum level was significantly increased in acne patients with severe disease symptoms. Furthermore, levels of total cholesterol (TC) and triglycerides (TG) were significantly increased, whereas high density lipoprotein cholesterol (HDL-C) level was significantly decreased in acne patients. The levels of apolipoprotein a varied widely in studied populations and no significant difference was found in the analyzed groups.ConclusionIn conclusion, we found that TNF-α expression increases in acne patients affected by TNF-α polymorphisms, and that the lipid profile is specifically disrupted in acne patients.     

Dihydrocapsaicin Attenuates Plaque Formation through a PPARγ/LXRα Pathway in apoE?/? Mice Fed a High-Fat/High-Cholesterol Diet

Aims

Atherosclerosis is a chronic inflammatory disease and represents the major cause of cardiovascular morbidity and mortality. There is evidence that dihydrocapsaicin (DHC) can exert multiple pharmacological and physiological effects. Here, we explored the effect of DHC in atherosclerotic plaque progression in apoE^−/− mice fed a high-fat/high-cholesterol diet.

Methods and Results

apoE^−/− mice were randomly divided into two groups and fed a high-fat/high-cholesterol diet with or without DHC for 12 weeks. We demonstrated that cellular cholesterol content was significantly decreased while apoA1-mediated cholesterol efflux was significantly increased following treatment with DHC in THP-1 macrophage-derived foam cells. We also observed that plasma levels of TG, LDL-C, VLDL-C, IL-1β, IL-6, TNF-α and CRP were markedly decreased while plasma levels of apoA1 and HDL-C were significantly increased, and consistent with this, atherosclerotic lesion development was significantly inhibited by DHC treatment of apoE^−/− mice fed a high-fat/high-cholesterol diet. Moreover, treatment with both LXRα siRNA and PPARγ siRNA made the up-regulation of DHC on ABCA1, ABCG1, ABCG5, SR-B1, NPC1, CD36, LDLR, HMGCR, apoA1 and apoE expression notably abolished while made the down-regulation of DHC on SRA1 expression markedly compensated. And treatment with PPARγ siRNA made the DHC-induced up-regulation of LXRα expression notably abolished while treatment with LXRα siRNA had no effect on DHC-induced PPARγ expression.

Conclusion

These observations provide direct evidence that DHC can significantly decrease atherosclerotic plaque formation involving in a PPARγ/LXRα pathway and thus DHC may represent a promising candidate for a therapeutic agent for the treatment or prevention of atherosclerosis.     

Surface study of apoB1694�C1880, a sequence that can anchor apoB to lipoproteins and make it nonexchangeable

Apolipoprotein B (apoB) is a nonexchangeable apolipoprotein. During lipoprotein assembly, it recruits phospholipids and triacylglycerols (TAG) into TAG-rich lipoprotein particles. It remains bound to secreted lipoproteins during lipid metabolism in plasma. The β1 region (residues 827–1880) of apoB has a high amphipathic β strand (AβS) content and is proposed to be one region anchoring apoB to lipoproteins. The AβS-rich region between apoB37 and apoB41 (residues 1694–1880) was cloned, expressed, and purified. The interfacial properties were studied at the triolein/water (TO/W) and air/water (A/W) interfaces. ApoB[37–41] is surface-active and adsorbs to the TO/W interface. After adsorption the unbound apoB[37–41] was removed from the aqueous phase. Adsorbed apoB[37–41] did not desorb and could not be forced off by increasing the surface pressure up to 23 mN/m. ApoB[37–41] adsorbed on the TO/W interface was completely elastic when compressed and expanded by ±13% of its area. On an A/W interface, the apoB[37–41] monolayer became solid when compressed to 4 mN/m pressure indicating extended β-sheet formation. It could be reversibly compressed and expanded between low pressure and its collapse pressure (35 mN/m). Our studies confirm that the AβS structure of apoB[37–41] is a lipid-binding motif that can irreversibly anchor apoB to lipoproteins.     

DHA attenuates postprandial hyperlipidemia via activating PPARα in intestinal epithelial cells

It is known that peroxisome proliferator-activated receptor (PPAR)α, whose activation reduces hyperlipidemia, is highly expressed in intestinal epithelial cells. Docosahexaenoic acid (DHA) could improve postprandial hyperlipidemia, however, its relationship with intestinal PPARα activation is not revealed. In this study, we investigated whether DHA can affect postprandial hyperlipidemia by activating intestinal PPARα using Caco-2 cells and C57BL/6 mice. The genes involved in fatty acid (FA) oxidation and oxygen consumption rate were increased, and the secretion of triacylglyceride (TG) and apolipoprotein B (apoB) was decreased in DHA-treated Caco-2 cells. Additionally, intestinal FA oxidation was induced, and TG and apoB secretion from intestinal epithelial cells was reduced, resulting in the attenuation of plasma TG and apoB levels after oral administration of olive oil in DHA-rich oil-fed mice compared with controls. However, no increase in genes involved in FA oxidation was observed in the liver. Furthermore, the effects of DHA on intestinal lipid secretion and postprandial hyperlipidemia were abolished in PPARα knockout mice. In conclusion, the present work suggests that DHA can inhibit the secretion of TG from intestinal epithelial cells via PPARα activation, which attenuates postprandial hyperlipidemia.     

Diet-induced weight loss in overweight or obese women and changes in high-density lipoprotein levels and function

Diet-induced weight loss in women may be associated with decreases not only in plasma levels of low-density lipoprotein cholesterol (LDL-C), but also in high-density lipoprotein cholesterol (HDL-C). Whether a decrease in HDL-C is associated with altered HDL function is unknown. One hundred overweight or obese women (age 46 ± 11 years, 60 black; 12 diabetic) were enrolled in the 6-month program of reduced fat and total energy diet and low-intensity exercise. Serum cholesterol efflux capacity was measured in (3)H-cholesterol-labeled BHK cells expressing ABCA1, ABCG1, or SR-B1 transporters and incubated with 1% apolipoprotein B (apoB)-depleted serum. Antioxidant properties of HDL were estimated by paraoxonase-1 (PON1) activity and oxygen radical absorbance capacity (ORAC). Endothelial nitric oxide synthase (eNOS) activation was measured by conversion of L-arginine to L-citrulline in endothelial cells incubated with HDL from 49 subjects. Participants achieved an average weight loss of 2.2 ± 3.9 kg (P < 0.001), associated with reductions in both LDL-C (-6 ± 21 mg/dl, P = 0.004) and HDL-C (-3 ± 9 mg/dl, P = 0.016). Cholesterol efflux capacity by the ABCA1 transporter decreased by 10% (P = 0.006); efflux capacities by the ABCG1 and SR-B1 transporters were not significantly altered. ORAC decreased by 15% (P = 0.018); neither PON1 activity nor eNOS activation was significantly altered by reduction in HDL-C. Findings were similar for diabetic and nondiabetic subjects. Diet-induced weight loss in overweight or obese women is associated with a decrease in HDL-C levels, but overall HDL function is relatively spared, suggesting that decrease in HDL-C in this setting is not deleterious to cardiovascular risk.     

Effects of R219K polymorphism of ATP-binding cassette transporter 1 gene on serum lipids ratios induced by a high-carbohydrate and low-fat diet in healthy youth

Background

Diets are the important players in regulating plasma lipid profiles. And the R219K polymorphism at the gene of ATP-binding cassette transporter 1(ABCA1) was reported to be associated with the profiles. However, no efforts have been made to investigate the changes of lipid profiles after a high-carbohydrate and low-fat diet in different subjects with different genotypes of this polymorphism. This study was to evaluate the effects of ABCA1 R219K polymorphism on serum lipid and apolipoprotein (apo) ratios induced by a high-carbohydrate/low-fat (high-CHO) diet. After a washout diet of 54.1% carbohydrate for 7 days, 56 healthy young subjects (22.89 ± 1.80 years old) were given a high-CHO diet of 70.1% carbohydrate for 6 days. Height, weight, waist circumference, hip circumference, glucose (Glu), triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apoA-1 and apoB-100 were measured on the 1^st, 8^th and 14^th days of this study. Body mass index (BMI), waist-to-hip ratios (WHR), log(TG/HDL-C), TC/HDL-C, LDL-C/HDL-C and apoA-1/apoB-100 were calculated. ABCA1 R219K was analyzed by a PCR-RFLP method.

Results

The results indicate that the male subjects of all the genotypes had higher WHR than their female counterparts on the 1^st, 8^th and 14^th days of this study. The male K carriers had higher log(TG/HDL-C) and TC/HDL-C than the female carriers on the 1^st and 14^th days, and higher LDL-C/HDL-C on the 14^th day. When compared with that on the 8^th day, TC/HDL-C was decreased regardless of the genotypes and genders on the 14^th day. Log(TG/HDL-C) was increased in the males with the RR genotype and the female K carriers. Lowered BMI, Glu and LDL-C/HDL-C were found in the male K carriers, but only lowered BMI in the female K carriers and only lowered LDL-C/HDL-C in the females with the RR genotype.

Conclusions

These results suggest that ABCA1 R219K polymorphism is associated differently in males and females with elevated log(TG/HDL-C) and decreased LDL-C/HDL-C induced by the high-CHO diet.