RESUMO
Perfluorooctane sulfonate (PFOS), an artificial fluorosurfactant and global contaminant, is used widely in various consumer products. In this study, we investigated the function of estrogen receptor ß (ERß) in PFOS-induced bile acid and cholesterol metabolism disorders and gut microbiome using ERß knockout mice that were exposed to PFOS by gavage. Our results showed that a daily dose of 5 mg PFOS/kg significantly induced hydropic degeneration and vacuolation in hepatic cells, reduced bile acid, and cholesterol levels in liver tissue, and influenced the abundance and composition of gut microbiota. Notably, ERß deficiency not only ameliorated morphological alterations of hepatocytes but also relieved disorders in bile acids and cholesterol metabolism caused by PFOS. Furthermore, the changes in the gut microbiome by PFOS were also modulated. The relative transcript abundance of key genes involved in bile acid and cholesterol metabolism exhibited similar changes. In HepG2 cells, PFOS increased ERß expression, which could be blocked by adding PHTPP (a selective antagonist of ERß). Our study thus provides new evidence that ERß mediates PFOS-induced hepatotoxicity.
Assuntos
Ácidos Alcanossulfônicos/toxicidade , Receptor beta de Estrogênio/metabolismo , Animais , Fluorocarbonos/toxicidade , Fígado/metabolismo , CamundongosRESUMO
BACKGROUND: Organochlorine pesticides (OCPs) are one kind of persistent organic pollutants. Although they are reported to be associated with metabolic disorders, the underlying mechanism is unclear. We explored the association of OCPs with gallstone disease and its influence on hepatic lipid metabolism. MATERIALS AND METHODS: OCPs levels in omentum adipose tissues from patients with and without gallstone disease between 2008 and 2011 were measured by GC-MS. Differences of gene expression involved in hepatic lipid metabolism and hepatic lipids content were compared in liver biopsies between groups with high and low level of OCPs. Using HepG2 cell lines, the influence on hepatic lipid metabolism by individual OCP was evaluated in vitro. RESULTS: In all patients who were from non-occupational population, there were high levels of ß-hexachlorocyclohexane (ß-HCH) and p',p'-dichloroethylene (p',p'-DDE) accumulated in adipose tissues. Both ß-HCH and p', p'-DDE levels were significantly higher in adipose tissues from patients with gallstone disease (294.3± 313.5 and 2222± 2279 ng/g of lipid) than gallstone-free controls (282.7± 449.0 and 2025±2664 ng/g of lipid, P< 0.01) and they were strongly related with gallstone disease (P for trend = 0.0004 and 0.0138). Furthermore, higher OCPs in adipose tissue led to increase in the expression of hepatic cholesterol transporters ABCG5 and G8 (+34% and +27%, P< 0.01) and higher cholesterol saturation index in gallbladder bile, and induced hepatic fatty acids synthesis, which was further confirmed in HepG2 cells. CONCLUSIONS: OCPs might enhance hepatic secretion of cholesterol into bile via ABCG5/G8 which promoting gallstone disease as well as lipogenesis.
Assuntos
Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/biossíntese , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/biossíntese , Poluentes Ambientais/efeitos adversos , Cálculos Biliares/induzido quimicamente , Lipogênese/efeitos dos fármacos , Lipoproteínas/biossíntese , Praguicidas/efeitos adversos , Adulto , Idoso , Povo Asiático , Poluentes Ambientais/análise , Feminino , Cálculos Biliares/metabolismo , Humanos , Hidrocarbonetos Clorados/efeitos adversos , Hidrocarbonetos Clorados/análise , Masculino , Pessoa de Meia-Idade , Praguicidas/análiseRESUMO
Niemann Pick Type C1 Like 1 (NPC1L1) protein plays a key role in intestinal and hepatic cholesterol metabolism in humans. Genetic variation in NPC1L1 has been widely studied in recent years. We analyzed NPC1L1 single nucleotide polymorphisms in Chinese gallstone disease patients to investigate their association with gallstone disease. NPC1L1 mRNA expression was also measured in liver biopsies from patients with cholesterol gallstone disease and compared between genotypes. The G allele of the g1679C>G (rs2072183) polymorphism was significantly more prevalent in patients with gallstones compared with gallstone-free subjects. Moreover, patients carrying the G allele had lower hepatic NPC1L1 mRNA expression and higher biliary cholesterol (molar percentages) and cholesterol saturation index. Our study suggests that the G allele of the NPC1L1 polymorphism g1679C>G may be a positive marker of gallstone formation risk.
Assuntos
Cálculos Biliares/genética , Predisposição Genética para Doença , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único/genética , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Alelos , China , Feminino , Genótipo , Haplótipos/genética , Humanos , Lipoproteínas/genética , Masculino , Proteínas de Membrana TransportadorasRESUMO
BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are a group of chemicals that can induce oxidative stress and related cytotoxicity. Whether environmental exposure of PAHs has effects on asthma in the general population is still unclear. This study investigated the association of urinary PAHs with asthma in U.S. children. METHODS: 15 447 children who participated in the US National Health and Nutrition Examination Survey 2001-2008 and 2011-2012 were studied. Ten urinary PAHs were analyzed for their association with asthma or asthma related symptoms. Multivariate logistic regression was applied to assess associations between urinary PAHs and asthma adjusted for age, gender, ethnicity, body mass index and the poverty income ratio. RESULTS: When stratified by age and sex, we found a remarkable association between urinary 2-phenanthrene and diagnosed asthma in boys (OR: 2.353, 95% CI: 1.156-4.792; P = 0.021) aged 13-19 years old. Positive association was observed between ever wheeze and 4-phenanthrene among girls aged 13-19 years (OR: 4.086, 95% CI: 1.326-12.584, P = 0.043). Moreover, an overall positive association between 1-pyrene and diagnosed asthma was observed. However, no association existed between levels of 1-napthol, 2-napthol, 3-fluorene, 2-fluorene, 3-phenanthrene, 1-phenanthrene or 9-fluorene with asthma or asthma symptom in this population. CONCLUSIONS: This data provide epidemiological evidences that urinary PAHs are positively associated with asthma in children aged 6-19 years. However, the underlying mechanisms still need further exploration.
Assuntos
Asma/urina , Hidrocarbonetos Policíclicos Aromáticos/urina , Adolescente , Criança , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino , Inquéritos Nutricionais , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: Little is known regarding the effects of environmental exposure of chemicals on androgenic system in the general population. We studied 5,107 subjects included in the National Health and Nutrition Examination Survey (2011-2012). METHODS: Urinary, serum, and blood levels of 15 subclasses comprising 110 individual chemicals were analyzed for their association with serum testosterone levels. The subjects were divided into high and low testosterone groups according to the median testosterone concentration (374.51 ng/dL). Odds ratios (ORs) of individual chemicals in association with testosterone were estimated using logistic regression after adjusting for age, ethnicity, cotinine, body mass index, creatinine, alcohol, and the poverty income ratio. RESULTS: Adjusted ORs for the highest versus lowest quartiles of exposure were 2.12 (95% CI: 1.07, 4.21; Ptrend = 0.044), 1.84 (95% CI: 1.02, 3.34; Ptrend = 0.018) for the association between urinary mandelic acid, and strontium quartiles with low testosterone concentrations in adult men, respectively. However, no association was observed for the remaining chemicals with testosterone. CONCLUSIONS: The National Health and Nutrition Examination Survey data suggest that elevations in urinary mandelic acid, and strontium levels are negatively related to low serum testosterone levels in adult men.
Assuntos
Ácidos Mandélicos/urina , Vigilância em Saúde Pública , Estrôncio/urina , Testosterona/sangue , Adulto , Idoso , Exposição Ambiental , Poluentes Ambientais , Etnicidade , História do Século XXI , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Razão de Chances , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
Phyto-oestrogens are a family of plant-derived xeno-oestrogens that appear to have beneficial effects on human health. To date, no data are available about phyto-oestrogen consumption affecting liver health in a population. The present study aimed to explore the relationship of urinary phyto-oestrogen metabolites with serum liver enzymes in US adults. A nationally representative sample of US adults in the National Health and Nutrition Examination Survey (NHANES) 2003-10 was analysed. The cross-sectional study sample consisted of 6438 adults with data on urinary phyto-oestrogen levels, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and γ-glutamyl transaminase (GGT) concentrations and data on other potential confounders. Multivariate logistic regression and linear regression were applied to assess associations between urinary phyto-oestrogen levels and ALT, AST, ALP and GGT concentrations. We found a remarkable association between urinary enterolactone and GGT in both adult males (OR 0.37, 95 % CI 0.22, 0.61; P= 0.003) and females (OR 0.37, 95 % CI 0.26, 0.54; P= 0.009). Moreover, elevated enterolactone levels were inversely associated with ALT and AST levels in adult males. However, no association was present between levels of urinary daidzein, O-desmethylangolensin, equol, enterodiol or genistein with liver enzyme levels in this population. The present study results provide epidemiological evidence that urinary enterolactone levels are associated with liver GGT levels in humans. This suggests a potential protective effect of enterolactone on human liver function. However, the underlying mechanisms still need further investigation.
Assuntos
4-Butirolactona/análogos & derivados , Lignanas/urina , Fígado/enzimologia , Inquéritos Nutricionais , 4-Butirolactona/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Aspartato Aminotransferases/sangue , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fitoestrógenos/urina , Estados Unidos , gama-Glutamiltransferase/sangueRESUMO
Neochamaejasmin A, isolated from Stellera chamaejasme L., has been widely used in China. Gut microbiota represent the first barrier against xenobiotics. This study aimed to evaluate the effects of subchronic exposure to neochamaejasmin A on the composition of gut microbiota. We found that neochamaejasmin A altered 21 OTUs in female rats and 46 OTUs in male rats. Among these OTUs, OTU86, OTU338 and OTU482 were shared in neochamaejasmin A-fed groups in both genders, implying that neochamaejasmin A might promote the growth of these three genera. In contrast, little or no effect on 226 OTUs was observed at all doses in both genders, suggesting their resistance to neochamaejasmin A. These findings could help improve our understanding of the health effects of neochamaejasmin A and provide an example of the risk assessment of pharmaceuticals or food contaminants on the gut microbiota composition.
Assuntos
Biflavonoides/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Colo/microbiologia , Fezes/microbiologia , Feminino , Masculino , Filogenia , Ratos Sprague-DawleyRESUMO
BACKGROUND: The association of the aldehyde dehydrogenases-2 (ALDH2) Glu504Lys polymorphism (also named Glu487Lys, or rs671) and cancers has been investigated. This meta-analysis aims to comprehensively assess the influence of this polymorphism on the overall cancer risk. METHODS: Eligible publications were retrieved according to inclusion/exclusion criteria and the data were analyzed using the Review Manager software (V5.2). RESULTS: A meta-analysis based on 51 case-control studies consisting of 16774 cases and 32060 controls was performed to evaluate the association between the ALDH2 Glu504Lys polymorphism and cancer risk. The comparison of genotypes Lys+ (Lys/Lys and Lys/Glu) with Glu/Glu yielded a significant 20% increased cancer risk (OR = 1.20, 95%CI: 1.03-1.39, P = 0.02, I2 = 92%). Subgroup analysis by cancer type indicated a significantly increased UADT cancer risk (OR = 1.39, 95%CI: 1.11-1.73, P = 0.004, I2 = 94%) in individuals with the Lys+ genotypes. Subgroup analysis by country indicated that individuals from Japan with the Lys+ genotypes had a significant 38% increased cancer risk (OR = 1.38, 95%CI: 1.12-1.71, P = 0.003, I2 = 93%). CONCLUSIONS: Our results indicated that the ALDH2 Glu504Lys polymorphism is a susceptible loci associated with overall cancers, especially esophageal cancer and among Japanese population.
Assuntos
Aldeído Desidrogenase/genética , Alelos , Predisposição Genética para Doença , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Aldeído-Desidrogenase Mitocondrial , Substituição de Aminoácidos , Estudos de Casos e Controles , Estudos de Associação Genética , Humanos , Razão de Chances , Viés de PublicaçãoRESUMO
Phyto-oestrogens are a family of plant-derived xeno-oestrogens that have been shown to prevent cancer in some studies. Whether phyto-oestrogen intake affects obesity status in a population is still unclear. In the present cross-sectional study, we examined the association of urinary phyto-oestrogen metabolites with obesity and metabolic parameters in children and adults. Data from 1294 children (age 6-19 years) and from 3661 adults (age ≥ 20 years) who participated in the US National Health and Nutrition Examination Survey 2001-10 were analysed. Multivariate logistic regression was applied to investigate the associations of BMI, waist circumference, serum metabolites (total cholesterol, HDL-cholesterol, LDL-cholesterol, TAG, fasting glucose and fasting insulin) and the metabolic syndrome with urinary phyto-oestrogen levels. When stratified by age and sex, we found a stronger association (OR 0·30, 95 % CI 0·17, 0·54; P< 0·001) between urinary enterolactone levels and obesity in adult males (age 20-60 years) than in children (age 12-19 years) or the elderly (age >60 years) in the same survey. However, no associations with urinary daidzein, O-desmethylangolensin, equol, enterodiol or genistein were found in the overall population. We also found that the elevation of enterolactone levels was inversely associated with TAG levels, fasting glucose levels, fasting insulin levels and the metabolic syndrome in males aged 20-60 years, but positively associated with HDL-cholesterol levels. The present results provide epidemiological evidence that urinary enterolactone is inversely associated with obesity in adult males.
Assuntos
4-Butirolactona/análogos & derivados , Regulação para Baixo , Lignanas/urina , Síndrome Metabólica/urina , Obesidade/urina , Fitoestrógenos/urina , 4-Butirolactona/urina , Adolescente , Adulto , Fatores Etários , Idoso , Índice de Massa Corporal , Criança , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Caracteres Sexuais , Estados Unidos , Circunferência da Cintura , Adulto JovemRESUMO
BACKGROUND: It is unclear whether liver transplantation is associated with an increased incidence of post-transplant head and neck cancer. This comprehensive meta-analysis evaluated the association between liver transplantation and the risk of head and neck cancer using data from all available studies. METHODS: PubMed and Web of Science were systematically searched to identify all relevant publications up to March 2014. Standardized incidence ratio (SIR) and 95% confidence intervals (CIs) for risk of head and neck cancer in liver transplant recipients were calculated. Tests for heterogeneity, sensitivity, and publishing bias were also performed. RESULT: Of the 964 identified articles, 10 were deemed eligible. These studies included data on 56,507 patients with a total follow-up of 129,448.9 patient-years. SIR for head and neck cancer was 3.836-fold higher (95% CI 2.754-4.918, P = 0.000) in liver transplant recipients than in the general population. No heterogeneity or publication bias was observed. Sensitivity analysis indicated that omission of any of the studies resulted in an SIR for head and neck cancer between 3.488 (95% CI: 2.379-4.598) and 4.306 (95% CI: 3.020-5.592). CONCLUSIONS: Liver transplant recipients are at higher risk of developing head and neck cancer than the general population.
Assuntos
Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/etiologia , Transplante de Fígado/efeitos adversos , Transplantados , Humanos , Incidência , Razão de Chances , Viés de PublicaçãoRESUMO
BACKGROUND: The CYP7A1 gene polymorphism has been reported to be associated with gallbladder stone disease (GSD) and serum lipid levels, but the results were inconsistent. This meta-analysis aimed to evaluate the influence of the -204A>C polymorphism in the promoter of CYP7A1 gene on the GSD and serum lipid levels. METHODS: According to inclusion/exclusion criteria, eligible studies on CYP7A1 gene -204A>C polymorphism of serum lipid levels and the risk of GSD were retrieved. Depending on the between-study heterogeneity, the fixed- or random-effects model was applied, and the data were analyzed using the RevMan software (V5.2). RESULTS: Five studies totaling 830 GSD patients and 882 healthy controls were used to evaluate the relation of CYP7A1 -204A>C polymorphism with GSD. Overall comparison of alleles A with C in all study population yielded 5% but non-significant increased risk of GSD (OR=1.05, 95% CI: 0.91 - 1.22, P=0.48). Subgroup analysis by ethnic differences did not show any association between CYP7A1 -204A>C polymorphism and GSD either. Four studies totaling 802 cases and 691 controls were used to assess the relation of CYP7A1 -204A>C polymorphism with serum lipid levels. All the subjects were from the Asian population. The pooled effects indicated that AC genotype had higher levels of TG than AA (MD=-0.42, 95% CI: -0.76 - -0.08, P=0.01). CC genotype in cases had higher levels of TC (MD=0.65, 95% CI: 0.25 - 1.05, P=0.001) and LDL-C (MD=0.40, 95% CI: 0.06 - 0.73, P=0.02) than AA, AA (MD = -0.35, 95% CI: -0.60 - -0.10, P=0.007) and AC (MD=-0.35, 95% CI: -0.61 - -0.08, P=0.01) genotypes in controls had higher levels of TC than CC, and AA genotype in controls had higher levels of HDL-C than CC (MD = -0.15, 95% CI: -0.21 - -0.09, P<0.00001). CONCLUSIONS: The CYP7A1 -204A>C polymorphism is significantly associated with serum lipid levels in Asian population, but not gallbladder stone disease.
Assuntos
Colesterol 7-alfa-Hidroxilase/genética , Cálculos Biliares/genética , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Cálculos Biliares/sangue , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Regiões Promotoras Genéticas , Fatores de RiscoRESUMO
BACKGROUND: In this study, we evaluated the association between these polymorphisms and gallstone disease using meta-analysis and compared the hepatic ABCG5/G8 mRNA expression and biliary lipids composition in patients with different genotypes of T400K and Y54C. METHODS: Data were analyzed using the Stata/SE 11.0 software and a random- effects model was applied irrespective of between-study heterogeneity. Hepatic mRNA expression of ABCG5/G8 genes in 182 patients with gallstone disease and 35 gallstone-free patients who underwent cholecystectomy were determined using real-time PCR. Genotypes of Y54C and T400K in the ABCG8 gene were determined by allelic discrimination using either genomic DNA or hepatic cDNA as template by Taqman assays. Biliary compostion in gallbladder bile was assayed in these patients as well. RESULTS: Ten papers including 13 cohorts were included for the final analysis. In the genotype model, the overall association between genotype with gallstone was significant for D19H (ORâ=â2.43, 95%CI: 2.23-2.64, P<0.001), and for Y54C (ORâ=â1.36, 95%CI: 1.01-1.83, Pâ=â0.044), or T400K (ORâ=â1.17, 95%CI: 0.96-1.43. Pâ=â0.110). In allele model, minor alleles of D19H polymorphism (allele D: ORâ=â2.25, 95%CI: 2.10-2.42, P<0.001) and of T400K polymorphism (allele K: ORâ=â1.18, 95%CI: 1.06-1.31, P<0.001) were related with an increased risk of gallstone disease. However, minor allele of Y54C polymorphism (allele Y, ORâ=â1.08, 95%CI: 0.96-1.21, Pâ=â0.146) was not related with gallstone disease. I(2) statistics indicated no significant between-study heterogeneity for all genetic models for any of the three polymorphisms. Funnel plot and Egger's test suggested the absence of publication bias as well. However, no association of T400K and Y54C polymorphism with hepatic ABCG8/G5 mRNA expression or biliary lipids composition was found. CONCLUSIONS: Our study showed strong association of D19H polymorphism with gallstone disease. T400K and Y54C polymorphism, though to a less extent, may also relate with gallstone disease.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Cálculos Biliares/genética , Lipoproteínas/genética , Polimorfismo de Nucleotídeo Único/genética , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Alelos , Bile/metabolismo , Estudos de Casos e Controles , Feminino , Cálculos Biliares/etiologia , Genótipo , Humanos , Lipídeos/genética , Lipoproteínas/metabolismo , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genéticaRESUMO
Acat2 [gene name: sterol O-acyltransferase 2 (SOAT2)] esterifies cholesterol in enterocytes and hepatocytes. This study aims to identify repressor elements in the human SOAT2 promoter and evaluate their in vivo relevance. We identified TG-interacting factor 1 (Tgif1) to function as an important repressor of SOAT2. Tgif1 could also block the induction of the SOAT2 promoter activity by hepatocyte nuclear factor 1α and 4α. Women have â¼ 30% higher hepatic TGIF1 mRNA compared with men. Depletion of Tgif1 in mice increased the hepatic Soat2 expression and resulted in higher hepatic lipid accumulation and plasma cholesterol levels. Tgif1 is a new player in human cholesterol metabolism.
Assuntos
Inativação Gênica , Proteínas de Homeodomínio/fisiologia , Proteínas Repressoras/fisiologia , Esterol O-Aciltransferase/genética , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Repressão Enzimática , Feminino , Cálculos Biliares/enzimologia , Fator 1-alfa Nuclear de Hepatócito/fisiologia , Fator 4 Nuclear de Hepatócito/fisiologia , Proteínas de Homeodomínio/metabolismo , Humanos , Lipídeos/sangue , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regiões Promotoras Genéticas , Ligação Proteica , Caracteres Sexuais , Esterol O-Aciltransferase/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica , Esterol O-Aciltransferase 2RESUMO
We investigated whether: (1) liver X receptor (LXR)-driven induction of high-density lipoprotein cholesterol (HDL-C) and other LXR-mediated effects on cholesterol metabolism depend on intestinal cholesterol absorption; and (2) combined treatment with the LXR agonist GW3965 and the cholesterol absorption inhibitor ezetimibe results in synergistic effects on cholesterol metabolism that could be beneficial for treatment of atherosclerosis. Mice were fed 0.2 % cholesterol and treated with GW3965+ezetimibe, GW3965 or ezetimibe. GW3965+ezetimibe treatment elevated serum HDL-C and Apolipoprotein (Apo) AI, effectively reduced the intestinal cholesterol absorption and increased the excretion of faecal neutral sterols. No changes in intestinal ATP-binding cassette (ABC) A1 or ABCG5 protein expression were observed, despite increased mRNA expression, while hepatic ABCA1 was slightly reduced. The combined treatment caused a pronounced down-regulation of intestinal Niemann-Pick C1-like 1 (NPC1L1) and reduced hepatic and intestinal cholesterol levels. GW3965 did not affect the intestinal cholesterol absorption, but increased serum HDL-C and ApoAI levels. GW3965 also increased Apoa1 mRNA levels in primary mouse hepatocytes and HEPA1-6 cells. Ezetimibe reduced the intestinal cholesterol absorption, ABCA1 and ABCG5, but did not affect the serum HDL-C or ApoAI levels. Thus, the LXR-driven induction of HDL-C and ApoAI was independent of the intestinal cholesterol absorption and increased expression of intestinal or hepatic ABCA1 was not required. Inhibited influx of cholesterol via NPC1L1 and/or low levels of intracellular cholesterol prevented post-transcriptional expression of intestinal ABCA1 and ABCG5, despite increased mRNA levels. Combined LXR activation and blocked intestinal cholesterol absorption induced effective faecal elimination of cholesterol.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , HDL-Colesterol/metabolismo , Colesterol/metabolismo , Receptores Nucleares Órfãos/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Anticolesterolemiantes/farmacologia , Apolipoproteína A-I/sangue , Apolipoproteína A-I/metabolismo , Azetidinas/farmacologia , Benzoatos/farmacologia , Benzilaminas/farmacologia , Western Blotting , Linhagem Celular Tumoral , Células Cultivadas , Colesterol/sangue , HDL-Colesterol/sangue , Ezetimiba , Fezes/química , Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Lipoproteínas/genética , Lipoproteínas/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Receptores X do Fígado , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores Nucleares Órfãos/agonistas , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND AND AIMS: The association between gallstone disease and coronary artery atherosclerotic disease (CAD) remains unclear. To clarify their relationship, patients with CAD newly diagnosed by coronary angiography were investigated in this cross-sectional study. METHODS: The study cohort consisted of 1,270 patients undergoing coronary angiography for the first time between January 2007 and September 2011. Patients with ≥50% diameter stenosis in any major coronary artery on coronary angiography were defined as being CAD positive (nâ=â766) and those with no stenosis as CAD negative (nâ=â504). Multivariate logistic regression was used to investigate the relationship between gallstone disease and CAD. The odds ratios (OR) of factors associated with CAD were calculated. In addition, CAD-positive and CAD-negative patients were matched one-to-one by age, gender and metabolic syndrome (MetS), and the association between gallbladder disease and CAD was determined. RESULTS: The prevalence of gallstone disease was significantly higher in CAD-positive than in CAD negative patients (149/766 [19.5%] vs 57/504 [11.3%], P<0.01). Gallstone disease was significantly associated with CAD (adjusted ORâ=â1.59, 95% confidence interval [CI] 1.10-2.31). Following matched pairing of 320 patients per group, gallstone disease remained significantly associated with CAD (adjusted ORâ=â1.69, 95% CI: 1.08-2.65). CONCLUSION: Gallstone disease is strongly associated with CAD diagnosed by coronary angiography.
Assuntos
Angiografia Coronária , Doença da Artéria Coronariana , Cálculos Biliares , Idoso , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Estenose Coronária/complicações , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/epidemiologia , Estudos Transversais , Feminino , Cálculos Biliares/diagnóstico por imagem , Cálculos Biliares/epidemiologia , Cálculos Biliares/etiologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Fatty liver index (FLI) was recently established to predict non-alcoholic fatty liver disease (NAFLD) in general population, which is known to be associated with coronary artery atherosclerotic disease (CAD).This study aims to investigate whether FLI correlates with NAFLD and with newly diagnosed CAD in a special Chinese population who underwent coronary angiography. METHODS: Patients with CAD (n = 231) and without CAD (n = 482) as confirmed by coronary angiography were included. Among them, 574 patients underwent B-ultrosonography were divided into NAFLD group (n = 209) and non-NAFLD group (n = 365). Correlation between FLI and NAFLD was analyzed using pearson's correlation. The associations between FLI and NAFLD as well as CAD were assessed using logistic regression. The predictive accuracy of FLI for NAFLD was evaluated using receiver operating characteristics (ROC) curve analysis. RESULTS: FLI was significantly higher in NAFLD group (37.10 ± 1.95) than in non-NAFLD group (17.70 ± 1.04), P < 0.01. FLI correlated with NAFLD (r = 0.372, P < 0.001). The algorithm for FLI had a ROC-AUC of 0.721 (95% CI: 0.678-0.764) in the prediction of NAFLD. Logistic regression analysis showed that FLI was associated with NAFLD (adjusted OR = 1.038, 95% CI: 1.029-1.047, P < 0.01). The proportion of patients with CAD did not differ among the groups of FLI ≤ 30 (32.3%), 30-60 (31.0%), and ≥60 (35.3%). No significant association was found between FLI and CAD (adjusted OR = 0.992, 95% CI: 0.981-1.003 in men and OR = 0.987, 95% CI: 0.963-1.012 in women, P > 0.05). CONCLUSIONS: FLI showed good correlation with NAFLD in patients who underwent coronary angiography, but not with newly diagnosed CAD. This might be underestimated because some patients in non-CAD group may have other underlying cardiovascular diseases.
Assuntos
Índice de Massa Corporal , Doença da Artéria Coronariana/diagnóstico , Fígado Gorduroso/diagnóstico , Triglicerídeos/sangue , Circunferência da Cintura , gama-Glutamiltransferase/sangue , Algoritmos , Área Sob a Curva , Biomarcadores/sangue , China , Intervalos de Confiança , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Fígado Gorduroso/sangue , Fígado Gorduroso/diagnóstico por imagem , Feminino , Humanos , Modelos Logísticos , Masculino , Hepatopatia Gordurosa não Alcoólica , Razão de Chances , Curva ROC , Radiografia , UltrassonografiaRESUMO
UNLABELLED: The sterolin locus (ABCG5/ABCG8) confers susceptibility for cholesterol gallstone disease in humans. Both the responsible variant and the molecular mechanism causing an increased incidence of gallstones in these patients have as yet not been identified. Genetic mapping utilized patient samples from Germany (2,808 cases, 2,089 controls), Chile (680 cases, 442 controls), Denmark (366 cases, 766 controls), India (247 cases, 224 controls), and China (280 cases, 244 controls). Analysis of allelic imbalance in complementary DNA (cDNA) samples from human liver (n = 22) was performed using pyrosequencing. Transiently transfected HEK293 cells were used for [(3) H]-cholesterol export assays, analysis of protein expression, and localization of allelic constructs. Through fine mapping in German and Chilean samples, an â¼250 kB disease-associated interval could be defined for this locus. Lack of allelic imbalance or allelic splicing of the ABCG5 and ABCG8 transcripts in human liver limited the search to coding single nucleotide polymorphisms. Subsequent mutation detection and genotyping yielded two disease-associated variants: ABCG5-R50C (P = 4.94 × 10(-9) ) and ABCG8-D19H (P = 1.74 × 10(-10) ) in high pairwise linkage disequilibrium (r(2) = 0.95). [(3) H]-cholesterol export assays of allelic constructs harboring these genetic candidate variants demonstrated increased transport activity (3.2-fold, P = 0.003) only for the ABCG8-19H variant, which was also superior in nested logistic regression models in German (P = 0.018), Chilean (P = 0.030), and Chinese (P = 0.040) patient samples. CONCLUSION: This variant thus provides a molecular basis for biliary cholesterol hypersecretion as the mechanism for cholesterol gallstone formation, thereby drawing a link between "postgenomic" and "pregenomic" pathophysiological knowledge about this common complex disorder. (HEPATOLOGY 2012).
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Colesterol/metabolismo , Cálculos Biliares/genética , Lipoproteínas/genética , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Alelos , Processamento Alternativo , Estudos de Casos e Controles , Linhagem Celular , Cálculos Biliares/metabolismo , Predisposição Genética para Doença , Humanos , Desequilíbrio de LigaçãoRESUMO
BACKGROUND AND AIMS: Gallstone disease (GD) is a common disease of multigenetic origin; however, the major susceptibility loci for GD in human populations remain unidentified. This study aimed to identify the genetic factors contributing to gallstone development in Chinese. METHODS: A genome-wide scan was conducted in 12 Han Chinese GD families to identify linkage loci. The linkage region showing the highest logarithm of odds score encompasses the sterol 12α-hydroxylase gene (CYP8B1). Replication analysis with an independent sample of 192 GD patients and 192 unrelated, matched controls was carried out to verify the associations between CYP8B1 polymorphisms and GD. RESULTS: Three loci (D3S1266, D4S406, and D9S1682) showed suggestive or nominal evidence of linkage in all 12 GD families. The logarithm of odds score of D3S1266 reached 2.71 in the families with late-onset patients. The single nucleotide polymorphism rs3732860 in the 3'-untranslated region of CYP8B1 showed significant association to GD (P = 0.022), and carriers of the A allele had lower risk of GD (odds ratio = 1.46, 95% confidence interval: 1.055-2.034) compared with carriers of the G allele. CONCLUSIONS: The single nucleotide polymorphism rs3732860 in the 3'-untranslated region of the CYP8B1 gene is associated with risk of GD in Chinese Han and appears to be responsible for the observed linkage with D3S1266.
Assuntos
Regiões 3' não Traduzidas/genética , Povo Asiático/genética , Sistema Enzimático do Citocromo P-450/genética , Cálculos Biliares/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Alelos , Povo Asiático/etnologia , Estudos de Casos e Controles , Primers do DNA/química , Feminino , Cálculos Biliares/etnologia , Ligação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Análise de SequênciaRESUMO
BACKGROUND: Numerous studies have investigated the relationship between apolipoprotein (Apo) E gene polymorphisms and gallbladder stone disease (GSD) across ethnic populations; however, the results are often inconsistent. This meta-analysis aims to comprehensively evaluate the influence of a common ε2/ε3/ε4 polymorphism in Apo E gene on the risk of gallbladder stone disease. METHOD: Data were analyzed using the RevMan software (V5.1) and a random-effects model was applied irrespective of between-study heterogeneity. Publication bias was weighed using the fail-safe number. RESULTS: There were 17 study populations totaling 1773 cases and 2751 controls for ε2/ε3/ε4 polymorphism of Apo E gene. Overall comparison of alleles ε2 with ε3 in all study populations yielded a 16% decreased risk for GSD (95% confidence interval [95% CI]: 0.68-1.05; P=0.31; I(2)â=13%), and comparison of alleles ε4 with ε3 yielded a 25% increased risk (95% confidence interval [95% CI]: 0.97-1.61; P=0.0003; I(2)â=63%). Subgroup analysis by study design indicated that the magnitude of association in hospital-based studies was largely significantly strengthened for ε4 allelic model (odds ratio [OR] â=1.46; 95% CI: 1.05-2.02; p=0.0007; I(2)â=65%). Subgroup analysis by age of controls indicated a remarkably significant elevation in the magnitude of association in age >50 subgroups in ε4 allelic model (OR=1.50; 95% CI: 1.03-2.19; p=0.0009; I(2)â=72%). Moreover, subgroup analysis by cases gender indicated a reduction in the magnitude of association in male<30% studies for E2/2 genotypic model (OR=0.32; 95% CI: 0.07-1.49; p=0.16; I(2)â=45%). CONCLUSIONS: Our results reveal that Apo E gene ε4 allele is a risk factor of gallbladder stone disease, especially in elder people and Chinese population.
Assuntos
Apolipoproteína E2/genética , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Cálculos Biliares/genética , Predisposição Genética para Doença , Polimorfismo Genético , Adulto , Alelos , Povo Asiático , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Razão de Chances , Fenótipo , Isoformas de Proteínas , Fatores de RiscoRESUMO
OBJECTIVE: To identify the single nucleotide polymorphisms of human CYP8B1gene and explore the association of some of these SNPs with gallstone disease in Chinese population. METHODS: The exon and part of promoter were sequenced by a fluorescent labeling automatic method to identify and characterize the SNPs in Chinese population. For SNPs with an allelic frequency of over 10%, a case-control study was performed in patients and controls. RESULTS: Eleven SNPs were found within a 5119 bp region. Among them, 1 was in coding region, 5 in promoter and 5 in 3'-UTR. There were 3 novel SNPs and 12 SNPs in SNP database were not found. The allelic frequency of rs3732860 polymorphism showed a significant difference (P = 0.022) in the association study. The subjects with A allele had a significantly lower frequency of gallstone disease than those with G allele (OR = 1.465, 95%CI 1.055 - 2.034, P = 0.023). CONCLUSION: SNP rs3732860 of CYP8B1 gene is associated with gallstone disease in Chinese population. And A allele may play a protective role in the pathogenesis of gallstone.