Mechanisms for differences in lipolysis between human subcutaneous and omental fat cells.

Catecholamine-regulation of lipolysis and beta-adrenoceptor binding isoterms were studied in human sc and omental isolated fat cells from 24 subjects undergoing elective cholecystectomy. The lipolytic sensitivity of the nonselective beta-agonists epinephrine and isoprenaline as well as the selective agonists norepinephrine (beta 1) and terbutaline (beta 2) was significantly increased 5-10 times in omental fat cells. On the other hand, no regional difference in antilipolytic sensitivity was seen for the alpha 2 agonist clonidine. No regional difference in lipolytic action was seen when measuring the effect of forskolin, (Bu)2cAMP or enprofylline, which act at different postadrenoceptor steps in the lipolytic cascade. Lipolysis data showed no sex differences. A beta 1-pattern was seen in both regions when lipolysis dose-response curves were arranged in order of potency. Radioligand saturation experiments with the nonselective beta-antagonist 125I-cyanopindolol and competition experiments between this radioligand and the selective antagonists CGP-20,712-A (beta 1) and ICI-118551 (beta 2) showed a 2-fold increase in the amount of beta 1- and beta 2-adrenergic receptors in omental as compared to sc fat cells (P less than 0.02). Competition studies with the same radioligand and the nonselective beta-agonist isoprenaline showed no regional differences in terms of receptor affinity (Kd high 10 nM and Kd low 1 microM) or in relative fraction of receptors in the high affinity state (35%). It is concluded that an increased lipolytic sensitivity for beta 1- and beta 2-agonists can be due to an increase in the amount of the two adrenoceptor subtypes in omental fat cells and thereby explain why catecholamines are more lipolytic in omental cells than in sc fat cells.     

Calpain-10 gene polymorphism is associated with reduced beta(3)-adrenoceptor function in human fat cells

Polymorphism in the calpain-10 gene is linked to type 2 diabetes, insulin resistance, and decreased thermogenesis. In view of the role of beta-adrenoceptors in thermogenesis we investigated the relationship between beta(1)-, beta(2)-, and beta(3)-adrenoceptor-stimulated lipolysis in abdominal sc fat cells and 3 different previously described single nucleotide polymorphisms (SNPs) in the calpain-10 gene (SNP-19, SNP-43, and SNP-63). The study sample comprised 240 healthy subjects. A strong association between lipolytic beta(3)-receptor function in adipocytes and the SNP-19, which is a deletion/insertion (1/2) was observed in overweight subjects (body mass index, >25 kg/m(2)), but not in lean ones. No association was found between any of the polymorphisms and lipolytic function of either beta(1)- or beta(2)-receptors. Carriers of 1/1 in SNP-19 had 30-fold decreased lipolytic sensitivity of beta(3)-adrenoceptors in comparison to 1/2 or 2/2 carriers (P = 0.0019, by ANOVA). This was found in both genders and was not influenced by SNP-43 or SNP-63 in the calpain-10 gene or by the Trp(64)Arg polymorphism in the beta(3)-adrenoceptor gene. In conclusion, a deletion/insertion polymorphism in the calpain-10 gene (SNP-19) is associated with reduced beta(3)-adrenoceptor function in obesity. This could be of importance for regulating thermogenesis in overweight subjects.     

Effect of polymorphisms in the PPARGC1A gene on body fat in Asian Indians

OBJECTIVE: To evaluate whether polymorphisms in the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PPARGC1A) gene were related to body fat in Asian Indians. METHODS: Three polymorphisms of PPARGC1A gene, the Thr394Thr, Gly482Ser and +A2962G, were genotyped on 82 type 2 diabetic and 82 normal glucose tolerant (NGT) subjects randomly chosen from the Chennai Urban Rural Epidemiology Study using PCR-RFLP, and the nature of the variants were confirmed using direct sequencing. Linkage disequilibrium (LD) was estimated from the estimates of haplotypic frequencies using an expectation-maximization algorithm. Visceral, subcutaneous and total abdominal fat were measured using computed tomography, whereas dual X-ray absorptiometry was used to measure central abdominal and total body fat. RESULTS: None of the three polymorphisms studied were in LD. The genotype (0.59 vs 0.32, P=0.001) and allele (0.30 vs 0.17, P=0.007) frequencies of Thr394Thr polymorphism were significantly higher in type 2 diabetic subjects compared to those in NGT subjects. The odds ratio for diabetes (adjusted for age, sex and body mass index) for the susceptible genotype, XA (GA+AA) of Thr394Thr polymorphism, was 2.53 (95% confidence intervals: 1.30-5.04, P=0.009). Visceral and subcutaneous fat were significantly higher in NGT subjects with XA genotype of the Thr394Thr polymorphism compared to those with GG genotype (visceral fat: XA 148.2+/-46.9 vs GG 106.5+/-51.9 cm(2), P=0.001; subcutaneous fat: XA 271.8+/-167.1 vs GG 181.5+/-78.5 cm(2), P=0.001). Abdominal (XA 4521.9+/-1749.6 vs GG 3445.2+/-1443.4 g, P=0.004), central abdominal (XA 1689.0+/-524.0 vs GG 1228.5+/-438.7 g, P<0.0001) and non-abdominal fat (XA 18763.8+/-8789.4 vs GG 13160.4+/-4255.3 g, P<0.0001) were also significantly higher in the NGT subjects with XA genotype compared to those with GG genotype. The Gly482Ser and +A2962G polymorphisms were not associated with any of the body fat measures. CONCLUSION: Among Asian Indians, the Thr394Thr (G --> A) polymorphism is associated with increased total, visceral and subcutaneous body fat.     

Evidence for an important role of perilipin in the regulation of human adipocyte lipolysis

AIMS/HYPOTHESIS: We investigated the role of the adipocyte-specific protein perilipin for lipolysis in humans. METHODS: Perilipin protein content and lipolysis rates were measured in human subcutaneous fat cells of non-obese (n=10) and obese (n=117) women. Single nucleotide polymorphisms in the perilipin gene were examined in obese subjects. RESULTS: Basal and noradrenaline-induced rates of lipolysis were two to fourfold increased (p<0.01) and perilipin protein content decreased 50% (p=0.005) in adipocytes of the obese women. In subjects matched for body mass index and fat-cell volume, a high rate of lipolysis was associated with a low adipocyte content of perilipin (p=0.01). Adipocyte content of perilipin was inversely correlated with the circulating concentrations of glycerol (r=0.62) and non-esterified fatty acids (n=0.49). A gene polymorphism (rs891460 A/G) in intron 6 was common. In AA subjects basal and noradrenaline induced lipolysis were 50 to 100% times more rapid (p相似文献   

Influence of heredity for obesity on adipocyte lipolysis in lean and obese subjects

OBJECTIVE: To evaluate a possible influence of a hereditary trait for obesity on the regulation of adipocyte metabolism in vitro in subcutaneous fat cells in obese and non-obese subjects. DESIGN: A biopsy from abdominal subcutaneous fat was obtained from consecutive subjects with or without a family trait for obesity. A positive family history of obesity was considered present if one or more of the first degree relatives had a BMI of 27 kg/m2 or more. SUBJECTS: 67 non-obese and 60 obese subjects, age 19-60 y. A family trait for overweight was present in 42 of the lean subjects and in 50 of the obese subjects. MEASUREMENTS: Fat cells were isolated and incubated in vitro with isoprenaline (a non-selective beta-adrenoceptor agonist), forskolin (activates the adenylyl cyclase) and dibutyryl cyclic AMP (stimulates the protein kinase hormone-sensitive lipase complex). Glycerol release was measured and used as lipolytic index. RESULTS: Maximal lipolytic response per g triglycerides was about 50% lower in obese subjects both with and without a positive heredity and in non-obese subjects with a family trait for obesity as compared to non-obese subjects without such trait (P=0.0001). Fat cell volume was twice as high in obese as compared to lean subjects. Drug-induced maximal glycerol release per fat cell in the obese subjects, regardless of family history of obesity, reached a similar level, but did not exceed that of the lean group without heredity. CONCLUSIONS: Obesity is associated with catecholamine resistance with a relatively ineffective lipolysis in fat cells, and presence of a family history of obesity was not associated with a further suppression of lipolysis. In the lean subjects, heredity for obesity significantly influenced lipolysis to similar low levels as in the obese subjects.     

Significance of beta2-adrenergic receptor gene polymorphism in obesity and type 2 diabetes mellitus in Korean subjects

Catecholamines play a central role in the regulation of energy expenditure, in part stimulating lipid mobilization through lipolysis in fat cells. The beta(2)-adrenergic receptor (ADRB2) is a major lipolytic receptor in human fat cells, and a recent study has shown that common polymorphisms occurring in codons 16 and 27 of the ADRB2 gene are significantly associated with obesity and lipolytic ADRB2 function in adipose tissue. We investigated whether previously described human ADRB2 gene polymorphisms are associated with obesity and diabetes in Korean subjects. According to the World Health Organization (WHO) criteria for oral glucose tolerance testing, 57 subjects had normal glucose tolerance (NGT), 32 had impaired glucose tolerance (IGT), and 106 had diabetes mellitus. The nondiabetic group (including NGT and IGT) consisted of 46 obese (defined as those with body mass index [BMI] of >or= 27 kg/m(2)) and 43 nonobese subjects (BMI < 27 kg/m(2)). The subjects with diabetes consisted of 62 obese and 44 nonobese subjects. There was no significant difference between nonobese and obese subjects in the allele frequency of ADRB2 gene polymorphisms at codons 16 and 27. There were no significant differences in BMI, percentage body fat, waist-to-hip ratio (WHR), systolic blood pressure, diastolic blood pressure and concentrations of fasting plasma glucose, fasting serum insulin, serum low-density lipoprotein (LDL)-cholesterol, serum high-density lipoprotein (HDL)-cholesterol, serum triglyceride, and serum free fatty acids, according to ADRB2 gene polymorphisms at codons 16 and 27. The frequency of the Glu27 homozygote was 1.1%. These findings suggest that genetic variability in the ADRB2 gene may not be a major determinant for the development of obesity and diabetes in Koreans.     

Interleukin-1 system gene polymorphisms are associated with fat mass in young men

CONTEXT: There is growing evidence for interactions between the regulation of body fat and the immune system. Studies of knockout mice indicate that IL-1 has an antiobesity effect. OBJECTIVE: The objective of the study was to investigate our hypothesis that common polymorphisms of the IL-1 system, which are associated with IL-1 activity, also are associated with fat mass. DESIGN, SETTING, AND STUDY SUBJECTS: The Gothenburg Osteoporosis and Obesity Determinants (GOOD) study is a population-based cross-sectional study of 18- to 20-yr-old men (n = 1068), mostly Caucasian, from the Gothenburg area (Sweden). Three different polymorphisms, IL-1beta +3953 C/T, IL-1beta-31 T/C, and IL-1 receptor antagonist (IL-1RN) variable number tandem repeat of 86 bp, were investigated in relation to body fat mass. MAIN OUTCOME MEASURE: The main outcome measures were genotype distributions and their association with body fat mass in different compartments, measured with dual-energy x-ray absorptiometry. RESULTS: Carriers of the T variant (CT and TT) of the +3953 C to T (F(T) = 0.25) IL-1beta gene polymorphism had significantly lower total fat mass (P = 0.013) and also significantly reduced arm, leg, and trunk fat, compared with CC individuals. IL-1RN*2 carriers with two repeats of the IL-1RN variable number tandem repeat polymorphism had increased total fat (P = 0.036), serum leptin, and fat of trunk and arm as well as serum levels of IL-1RN and IL-1RN production ex vivo. The IL-1beta-31 polymorphism did not correlate with the fat measurements. CONCLUSIONS: The IL-1 system, recently shown to affect fat mass in experimental animals, contains gene polymorphisms that are associated with fat mass in young men.     

Adipose tissue metabolism in young and middle-aged men after control for total body fatness

The aim of this study was to compare the sc adipose tissue metabolism of young (29 +/- 4 yr) vs. middle-aged men (57 +/- 5 yr), once the concomitant variation in total adiposity was taken into account. For this purpose, sc abdominal and femoral adipose tissue lipoprotein lipase activities, as well as fat cell lipolytic responses, were investigated in 2 groups of 16 men, differing in age but displaying similar adipose tissue mass (within 2 kg) and sc abdominal adipose tissue area, measured by computed tomography (within 15 cm2). No difference was observed in adipose tissue lipoprotein lipase activity of young vs. middle-aged subjects, regardless of the adipose region considered. Epinephrine induced antilipolysis at low concentrations (10(-9) to 10(-7) mol/L) and a net lipolytic response at higher doses (10(-6) to 10(-5) mol/L), regardless of the subjects' age and the anatomic location of fat. In addition, the selective alpha2-adrenergic agonist, UK-14304, promoted a similar antilipolytic response in sc abdominal and femoral adipose cells from both groups. However, maximal lipolysis induced by isoproterenol (beta-adrenergic agonist) or by postadrenoceptor agents such as dibutyryl-cAMP, forskolin, and theophylline were lower in both adipose regions of middle-aged (as compared with young) men. No difference in the beta- or the alpha2-adrenoceptor sensitivity of sc adipose cells was observed between groups. These results indicate that there is, with age, a selective decrease in the lipolytic capacity to beta-adrenergic agonist, which seems to be caused by postadrenoceptor impairments. Because subjects in the 2 age-groups displayed similar body fatness, these alterations are independent from the age-expected increase in total adiposity.     

Polymorphisms of the renin-angiotensin system influence height in normotensive women in a Spanish population

The objective of this study was to analyze the influence of the polymorphisms G-6A of the angiotensinogen gene, insertion/deletion (I/D) of the angiotensin-converting enzyme, and C573T of the angiotensin II AT1 receptor gene on a healthy, middle-age population. A total of 370 (194 women) healthy normotensive Caucasian subjects, aged 25-50 yr old, were selected from the general population. A significant association was found between height and the C573T polymorphism in women (P < 0.001). After adjustment for age, this association remained significant (P < 0.002). Thus, the lowest height values were from subjects carrying TT genotype (CC, 1.627 +/- 0.008 m; CT, 1.595 +/- 0.006 m; TT, 1.586 +/- 0.010 m; P = 0.002). Likewise, the I/D polymorphism was associated with height (P = 0.002) in women. It remained significant after adjustment for age and the lowest height for the DD genotype (II, 1.629 +/- 0.011 m; ID, 1.603 +/- 0.006 m; DD, 1.591 +/- 0.007 m; P = 0.016). For both C573T and I/D polymorphisms, there was an allele dosage effect. Moreover, an additive and independent effect of the C573T polymorphism (P = 0.006) and the I/D polymorphism (P = 0.045) on height was observed. In contrast, no association with height was observed for the G-6A polymorphism. In conclusion, additive effects between polymorphisms of the renin-angiotensin system genes and height were observed in healthy women. These results should be studied by other groups in other populations and ethnic groups. Whether or not these associations need to be considered in the epidemiological studies analyzing the relationship between polymorphisms of the renin-angiotensin system genes and such height-influenced parameters as blood pressure merits further study.     

Age-related differences in messenger ribonucleic acid expression of key proteins involved in adipose cell differentiation and metabolism

This study was performed to compare the expression of key proteins [lipoprotein lipase (LPL), hormone-sensitive lipase (HSL), complement 3 (C3), and peroxisome proliferator-stimulated receptor-gamma (PPAR gamma)] involved in sc abdominal adipose tissue (AT) metabolism of young (n = 13) vs. middle-aged (n = 16) men. The sc abdominal AT-LPL activity as well as fat cell lipolysis were also measured in both groups of men. Young and middle-aged men displayed similar body weight and sc abdominal fat accumulation, measured by computed tomography. However, middle-aged men were characterized by a higher percent body fat (28 +/- 5% vs. 22 +/- 7%; P < 0.05) than young subjects. No difference between groups was observed in sc abdominal adipose tissue LPL activity. On the other hand, maximal lipolytic responses of sc abdominal adipocytes to isoproterenol (beta-adrenergic agonist) or to postadrenoceptor agents such as dibutyryl cAMP, forskolin, and theophylline were lower in middle-aged than in young men (P < 0.05). AT-LPL messenger ribonucleic acid (mRNA) levels were similar regardless of the subject's age. However, HSL, C3, and PPAR gamma mRNA levels were higher in middle-aged than in young individuals (P < 0.01-0.05). After correction for percent body fat, only HSL and C3 mRNA levels remained significantly different between groups (P < 0.05). Taken together, these results suggest that aging has an effect on the up-regulation of HSL and C3 mRNA levels, whereas PPAR gamma expression seems to be related mainly to increased adiposity.     

肾素-血管紧张素系统基因多态性与原发性高血压左心室肥厚关系的探讨

目的　探讨肾素 血管紧张素系统 (RAS)基因多态性与原发性高血压左心室肥厚 (EH LVH)的相关性以及在EH LVH产生中的多基因协同作用。方法　对 10 9例原发性高血压病 (EH)患者 ,采用聚合酶链反应 (PCR)以及聚合酶链反应 限制性片段长度多态性方法检测血液白细胞染色体DNA中血管紧张素转换酶 [ACE(I D) ]、血管紧张素原 [AGT(M2 35T) ]和血管紧张素Ⅱ 1型受体 [AT1 R(A116 6C) ]基因多态性 ;利用超声心动图检测左心室质量 (LVM)并计算左心室质量指数 (LVMI)。结果　ACE(I D)基因多态性D等位基因频率在EH LVH组中明显增高 (χ2 =4 .6 9,P=0 .0 30 ) ,男性EH患者中 ,ACE(I D)基因型构成比与LVH有关联 (χ2 =9.5 5 ,P =0 .0 0 8)。协同存在AGT TT型时 ,ACE(I D)基因多态性与EH LVH有关 (χ2 =6 .2 2 ,P =0 .0 4 4 ) ,且D等位基因在EH LVH明显增高 (χ2 =6 .91,P =0 .0 0 9) ,该类EH患者发生LVH的相对危险度增高 (OR :2 .5 0 ,95 %CI:1.2 5～ 5 .0 0 )。结论　ACE(I D)基因多态性D等位基因可能是LVH的独立危险因子。ACE基因多态性与AGT基因多态性之间的协同效应表明 ,同时携带AGT TT型时 ,具有ACE(I D)基因多态性D等位基因的EH患者更易发生LVH。     

Changes in fat cell size and in vitro lipolytic activity of abdominal and gluteal adipocytes after a one-year cross-sex hormone administration in transsexuals

We prospectively studied the effects of cross-sex hormone administration on fat cell size and in vitro lipolytic activity in subcutaneous abdominal and gluteal fat biopsies obtained from 19 male-to-female (M-F) transsexuals and 17 female-to-male (F-M) transsexuals. The amount of subcutaneous fat at the abdominal and gluteal levels was quantified with the use of magnetic resonance imaging (MRI). Before cross-sex hormone administration, M-F transsexuals had less subcutaneous fat with smaller fat cells compared with F-M transsexuals, with a higher baseline in vitro lipolytic activity expressed as glycerol release per milligram of triglyceride (TG) in the abdominal region (P < .05). Before cross-sex hormone treatment, no differences in lipolytic activity stimulated with arterenol (ART), isoproterenol (ISO), or ISO + insulin (INS) were observed between groups or regions. After a 1-year treatment with estrogens and antiandrogens in M-F transsexuals, subcutaneous fat areas on MRI and fat cell size were increased (P < .001) and reductions were observed in the basal lipolytic activity of gluteal and abdominal fat biopsies (P < .05). Following administration of testosterone to F-M transsexuals, subcutaneous fat and fat cell size at the gluteal and abdominal depots were decreased (P < .01) and basal lipolysis was increased significantly at the abdominal level (P < .05) but not at the gluteal level. In both M-F and F-M transsexuals, no effect of sex hormone administration was observed on stimulated lipolytic activities. In conclusion, regional sex differences in the amount of subcutaneous fat, adipocyte size, and in vitro basal lipolytic activity were demonstrated that could be largely reversed by cross-sex hormone treatment in adult subjects, providing evidence for their dependence on the sex steroid milieu.     

Adipocyte lipolysis in normal weight subjects with obesity among first-degree relatives

Summary In this study we investigated whether fat cell lipolysis could be involved in the aetiology of obesity by comparing non-obese subjects with (Hob) or without (Hnorm) a family trait for overweight. A family history of obesity was present when at least one of the first-degree relatives had body mass index of 27 kg/m² or more. Twenty-seven healthy, drugfree non-obese adult subjects were investigated; 13 were Hob and the remaining 14 were Hnorm. Eleven Hob had at least one obese parent. Isolated fat cells from abdominal subcutaneous adipose tissue were incubated in vitro. Glycerol release (lipolysis index), mRNA levels and enzymatic activity of hormone-sensitive lipase and radioligand binding to beta₁- and beta₂-adrenoceptors were determined. The lipolytic effects of noradrenaline (major endogenous lipolytic agent), isoprenaline (a non-selective beta-adrenoceptor agonist), forskolin (a direct activator of adenylyl cyclase) and dibutyryl cyclic AMP (activating protein kinase and thereby hormone-sensitive lipase) were reduced by about 50% (p from 0.001 to 0.01). The maximum activity of hormone-sensitive lipase was reduced 50% in Hob (p<0.05) and correlated with the lipolytic responsiveness of fat cells in the whole population (r=0.71). However, there was no difference between the groups in steady-state mRNA levels for the enzyme. Beta₁-, beta₂- and alpha₂-adrenoceptor sensitivity as well as beta₁- and beta₂-adrenoceptor numbers were normal in Hob. Fasting plasma insulin was 49.1 and 32.6 pmol/l, respectively in Hob and Hnorm (p=0.01). There was, however, no significant correlation between lipolysis in vitro and plasma insulin. Thus, lipolytic catecholamine resistance in fat cells, at least partly due to impaired function of hormone-sensitive lipase, is an adipocyte abnormality associated with a family tendency to obesity.     

NLRP2基因多态性与中国汉族人群1型糖尿病的关联研究

目的探讨在中国汉族人群中核苷酸结合寡聚化结构域样受体蛋白2(NLRP2)基因的单核苷酸多态性(SNP)与经典1型糖尿病(T1DM)的相关性。方法选取就诊于中南大学湘雅二医院代谢内分泌科的510例经典T1DM患者及本地区531名无血缘关系的健康志愿者为研究对象。利用质谱法对其NLRP2基因的rs1043673位点进行基因分型。两组间一般资料的比较采用Mann-Whitney U检验和χ2检验,T1DM患者组与对照组之间基因型及等位基因频率分布的比较采用χ2检验和logistic回归分析。NLRP2多态性与各项临床特征的分析采用Kruskal-Wallis H检验。结果NLRP2基因rs1043673位点的等位基因及基因型在两组之间的分布无明显差异。在T1DM患者中,rs1043673多态性与空腹C肽(P=0.029)、餐后2 h C肽(P=0.017)以及GADA的抗体滴度(P=0.043)均有关。结论NLRP2基因的rs1043673多态性与中国汉族T1DM患者的临床特征有关。     

Association of polymorphisms in the estrogen receptor alpha gene with body fat distribution

OBJECTIVE: To examine whether polymorphisms of the estrogen receptor (ER) alpha gene are associated with body fat distribution. DESIGN: Cross-sectional, epidemiological study of two single-nucleotide polymorphisms, a T --> C (PvuII) and an A --> G (XbaI), in the first intron of the ERalpha gene. SUBJECTS: A total of 2238 community-dwelling middle-aged and elderly Japanese population (age: 40-79 y). MEASUREMENTS: The ERalpha genotypes (by automated fluorescent allele-specific DNA primer assay system), anthropometric variables, fat mass (FM) and percentage FM (%FM) (by dual-energy X-ray absorptiometry). RESULTS: FM and waist were inversely associated with age (r=-0.630 and -0.504, respectively) in women with the GG genotype. On the other hand, waist circumference of the AA genotype was positively correlated with age (r=0.231). Thus, for middle-aged women (40-59 y) with the AG or GG genotype body mass index (BMI), %FM, FM, waist, hip and waist-to-hip ratio (WHR) were larger than those with the AA genotype. In particular, FM and waist were greater by 20% and 9%, respectively, for the GG genotype, compared to the AA genotype. Alternatively, FM and waist were smaller by 18% and 6%, respectively, in older women with the GG genotype, compared to the AA genotype. No effect was found among the A --> G polymorphisms for men. For both genders, no difference was found in any variables among the TT, TC and CC genotypes with the exception of BMI of older men (60-79 y). CONCLUSION: No association was found between the ERalpha gene polymorphisms and body fat distribution in men. For women, the A --> G polymorphism, in particular the GG genotype, may contribute to the development of upper-body obesity in middle-aged individuals, but may serve to decrease the whole-body and abdominal fat tissue of older individuals.     

A polymorphism regulates CYP4A11 transcriptional activity and is associated with hypertension in a Japanese population

CYP4A11 oxidizes arachidonic acid to 20-hydroxyeicosatetraenoic acid, a metabolite with renovascular and tubular function in humans. A previous study demonstrated a significant association between the CYP4A11 gene polymorphism and hypertension; however, the precise mechanism of the association has not been clarified. To assess the involvement of CYP4A11 in the pathogenesis of hypertension, we sought to identify a functional polymorphism of CYP4A11 and examined its impact on predisposition to hypertension in the Tanno-Sobetsu Study. The -845A/G polymorphism was identified in the promoter region of CYP4A11 by direct sequencing. Luciferase expression driven by the promoter of CYP4A11 containing the wild-type -845GG genotype was 30% lower than expression with the variant -845AA genotype. Gel mobility shift assays with nuclear protein extracts showed specific binding to probes containing the variant -845GG. To assess the effect of CYP4A11 polymorphisms on hypertension, we also carried out a case-control study using 4 single nucleotide polymorphisms (-845A/G, -366C/T, 7119C/T, and 8590T/C) in the Tanno-Sobetsu Study. The odds ratio for hypertension in participants with the AG+GG genotype of -845A/G was 1.42 (P=0.008), and the odds ratio for hypertension of the TT genotype of 7119C/T was 1.37 (P=0.037) after adjusting for confounding factors. The haplotype-based case-control analysis using 4 single nucleotide polymorphisms revealed a significant haplotype (G-C-T-T) that was significantly associated with hypertension, with an odds ratio of 1.44 (P=0.006) after adjusting for confounding factors. We have identified a functional variant (-845A/G) of CYP4A11 that is significantly associated with hypertension and that appears to be a novel candidate for a predisposing factor for hypertension.     

Metformin reduces lipolysis in primary rat adipocytes stimulated by tumor necrosis factor-alpha or isoproterenol

In patients with type 2 non-insulin-dependent diabetes mellitus (NIDDM), the biguanide, metformin, exerts its antihyperglycemic effect by improving insulin sensitivity, which is associated with decreased level of circulating free fatty acids (FFA). The flux of FFA and glycerol from adipose tissue to the blood stream primarily depends on the lipolysis of triacylglycerols in the adipocytes. Adipocyte lipolysis is physiologically stimulated by catecholamine hormones. Tumor necrosis factor-alpha (TNF-alpha), a cytokine largely expressed in adipose tissue, stimulates chronic lipolysis, which may be associated with increased systemic FFA and insulin resistance in obesity and NIDDM. In this study, we examined the role of metformin in inhibiting lipolytic action upon various lipolytic stimulations in primary rat adipocytes. Treatment with metformin attenuated TNF-alpha-mediated lipolysis by suppressing phosphorylation of extracellular signal-related kinase 1/2 and reversing the downregulation of perilipin protein in TNF-alpha-stimulated adipocytes. The acute lipolytic response to adrenergic stimulation of isoproterenol was also restricted by metformin. A high concentration of glucose in the adipocyte culture promoted the basal rate of glycerol release and significantly enhanced the lipolytic action stimulated by either TNF-alpha or isoproterenol. Metformin not only inhibits the basal lipolysis simulated by high glucose, but also suppresses the high glucose-enhanced lipolysis response to TNF-alpha or isoproterenol. The antilipolytic action in adipocytes could be the mechanism by which cellular action by metformin reduces systemic FFA concentration and thus improves insulin sensitivity in obese patients and the hyperglycemic conditions of NIDDM.     

Association of estrogen receptor-alpha gene polymorphisms with coronary artery disease in patients with familial hypercholesterolemia

To investigate the association of estrogen receptor (ER)-alpha gene polymorphisms with coronary artery disease (CAD), we studied 197 men and 98 postmenopausal women with heterozygous familial hypercholesterolemia. We examined the known polymorphisms, including PvuII, XbaI, TA repeat, and CA repeat, and identified 6 novel polymorphisms in the ER-alpha gene. The distributions of -1989T/G (a novel polymorphism in promoter B) and XbaI in intron 1 were associated with CAD in postmenopausal women and in men, with a higher frequency of the G/G genotype (P=0.03) or X1/X1 genotype (P=0.02) in the CAD group. The frequency of alleles of TA repeats >17 was found to be significantly higher in postmenopausal women with CAD than in those without CAD (P=0.04), but not in men. Logistic regression analysis with all coronary risk factors as covariates showed that the G/G genotype was a higher risk for CAD (odds ratio 4.5, 95% CI 1.0 to 19.5;P=0.04) but that X1/X1 was not. We conclude that -1989T/G or its linked polymorphisms in the ER-alpha gene may confer risk for CAD and that the G/G genotype may be an independent predictor for CAD in patients with familial hypercholesterolemia.     

Hematopoietic cell kinase gene polymorphisms and the risk of chronic obstructive pulmonary disease in a Chinese population

Hematopoietic cell kinase (Hck), a Src family kinase, has been recently suggested to be implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). The present study aims to analyze the association of polymorphism of Hck gene with COPD in a Chinese population. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and polymerase chain reaction-sequence-specific primer method (PCR-SSP) were used to type Hck polymorphisms in 120 patients with COPD and 100 healthy controls. There were significant differences in the genotype and allele distribution of -627 G/T polymorphism in Hck gene between cases and controls (P<.05). The GT genotype was associated with a significantly increased risk of COPD as compared with the GG genotype (Odds ratio [OR]=2.60, 95% confidence interval [CI]: 1.39-4.48; P=.002). Moreover, individuals carrying T allele had a significantly higher risk for developing COPD than those carrying G allele (OR=2.19, 95% CI: 1.26-3.79; P=.005). In haplotype analysis, compared with CG(deletion) haplotype, CT(insertion) haplotype was associated with a significantly increased risk of COPD (OR=2.66, 95% CI: 1.22-5.78; P=.011). These findings suggest the Hck gene polymorphisms may contribute to COPD susceptibility in Chinese population.