Urinary enterolactone associated with liver enzyme levels in US adults: National Health and Nutrition Examination Survey (NHANES).

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.

Urinary enterolactone is associated with obesity and metabolic alteration in men in the US National Health and Nutrition Examination Survey 2001-10.

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.

TG-interacting factor 1 acts as a transcriptional repressor of sterol O-acyltransferase 2.

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 ∼ 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.

Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus.

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 ∼250 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).

Increased incidence of head and neck cancer in liver transplant recipients: a meta-analysis.

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.

Relationship between CYP7A1 -204A>C polymorphism with gallbladder stone disease and serum lipid levels: a meta-analysis.

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.

Fatty liver index correlates with non-alcoholic fatty liver disease, but not with newly diagnosed coronary artery atherosclerotic disease in Chinese patients.

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.

Single nucleotide polymorphism rs3732860 in the 3'-untranslated region of CYP8B1 gene is associated with gallstone disease in Han Chinese.

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.

Hepatic Niemann-Pick C1-like 1.

PURPOSE OF REVIEW: The discovery of Niemann-Pick C1-like 1 (NPC1L1) and ezetimibe, a drug that lowers intestinal cholesterol absorption, has contributed to the recognition of the intestine as an important organ in whole-body cholesterol homeostasis. Unfortunately, the majority of the studies on NPC1L1 have been conducted in rodent models, which, in contrast to humans, do not express this protein in the liver. Thus the function of NPC1L1 in the liver is still not defined in detail. In this review, we discuss some of the recent progress in the understanding of the role of hepatic NPC1L1 in cholesterol metabolism. RECENT FINDINGS: Mice expressing human NPC1L1 in the liver have decreased biliary cholesterol concentration, suggesting the involvement of this protein in the hepatic reabsorption of biliary cholesterol. Studies in gallstone patients have shown that only women have decreased hepatic NPC1L1 expression, suggesting a possible role for the sex-related differences in cholesterol gallstone disease. Also, several transcription factors (e.g., sterol regulatory element-binding protein 2, hepatocyte nuclear factor 1α) appear to modulate the expression of NPC1L1. SUMMARY: Evidence suggests the involvement of NPC1L1 in biliary cholesterol uptake, HDL metabolism and cholesterol gallstone disease. Although difficult, studies in humans are required to further elucidate the function of this protein in the liver.

[Association of single nucleotide polymorphism in human CYP8B1 gene with gallstone disease].

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.

HNF1alpha and SREBP2 are important regulators of NPC1L1 in human liver.

Niemann-Pick C1-like 1 (NPC1L1), a key regulator of intestinal cholesterol absorption, is highly expressed in human liver. Here, we aimed to gain more insight into mechanisms participating in its hepatic regulation in humans. Correlation analysis in livers from Chinese patients with and without gallstone disease revealed strong positive correlations between NPC1L1 and sterol regulatory element binding protein 2 (SREBP2) (r = 0.74, P < 0.05) and between NPC1L1 and hepatic nuclear factor alpha (HNF4alpha) (r = 0.53, P < 0.05) mRNA expression. HNF4alpha is an upstream regulator of HNF1alpha; thus, we also tested whether HNF1alpha participates in the regulation of NPC1L1. We showed a dose-dependent regulation by SREBP2 on the NPC1L1 promoter activity and mRNA expression in HuH7 cells. Chromatin immunoprecipitation assay confirmed the binding of SREBP2 to the promoter in vivo. Surprisingly, HNF4alpha slightly decreased the NPC1L1 promoter activity but had no effect on its gene expression. By contrast, HNF1alpha increased the promoter activity and the gene expression, and an important HNF1 binding site was identified within the human NPC1L1 promoter. ChIP assays confirmed that HNF1alpha can bind to the NPC1L1 promoter in vivo.

Abolished synthesis of cholic acid reduces atherosclerotic development in apolipoprotein E knockout mice.

To investigate the effects of abolished cholic acid (CA) synthesis in the ApoE knockout model [apolipoprotein E (apoE) KO],a double-knockout (DKO) mouse model was created by crossbreeding Cyp8b1 knockout mice (Cyp8b1 KO), unable to synthesize the primary bile acid CA, with apoE KO mice. After 5 months of cholesterol feeding, the development of atherosclerotic plaques in the proximal aorta was 50% less in the DKO mice compared with the apoE KO mice. This effect was associated with reduced intestinal cholesterol absorption, decreased levels of apoB-containing lipoproteins in the plasma, enhanced bile acid synthesis, reduced hepatic cholesteryl esters, and decreased hepatic activity of ACAT2. The upregulation of Cyp7a1 in DKO mice seemed primarily caused by reduced expression of the intestinal peptide FGF15. Treatment of DKO mice with the farnesoid X receptor (FXR) agonist GW4064 did not alter the intestinal cholesterol absorption, suggesting that the action of CA in this process is confined mainly to formation of intraluminal micelles and less to its ability to activate the nuclear receptor FXR. Inhibition of CA synthesis may offer a therapeutic strategy for the treatment of hyperlipidemic conditions that lead to atherosclerosis.

Decreased NPC1L1 expression in the liver from Chinese female gallstone patients.

BACKGROUND: Cholesterol gallstone disease is a very common disease in both industrialized and developing countries. Many studies have found that cholesterol gallstones are more common in women than men. The molecular mechanisms underlying the relationship between female gallstone disease and hepatic sterol transporters are still undergoing definition and have not been evaluated in humans. AIMS: The aim of this study is to probe for underlying hepatic molecular defects associated with development of gallstones in female. METHODS/RESULTS: Fifty-seven nonobese, normolipidemic Chinese female gallstone patients (GS) were investigated with 12 age- and body mass index-matched female gallstone-free controls (GSF). The bile from the female GS had higher cholesterol saturation than that from the female GSF. The hepatic NPC1L1 mRNA levels were lower in female GS, correlated with SREBP2 mRNA. NPC1L1 downregulation was confirmed at protein levels. Consistently, immunohistochemistry showed decreased NPC1L1 expression in female GS. CONCLUSIONS: The decreased hepatic NPC1L1 levels in female GS might indicate a downregulated reabsorption of biliary cholesterol in the liver, which, in turn, leads to the cholesterol supersaturation of bile. Our data are consistent with the possibility that hepatic NPC1L1 may be mediated by SREBP2.

Increased NPC1L1 and ACAT2 expression in the jejunal mucosa from Chinese gallstone patients.

The incidence of cholesterol gallstones is a very common disease. The aim of this study is to probe for underlying intestinal molecular defects associated with development of gallstones. Twelve Chinese patients with cholesterol gallstone disease (GS) and 31 gallstone-free (GSF) patients were investigated. Quantitation of mRNA levels for individual genes in mucosal biopsies from jejunum was carried out with real-time PCR. The frequency of two SNPs in the ABCG8 gene (Y54C and T400K) was determined by allelic discrimination. The intestinal mRNA expression of NPC1L1 and ACAT2 were significantly higher in GS than GSF (P<0.05). No differences were observed concerning the levels for plasma lipids, plant sterols and 7alpha-hydroxy-4-cholesten-3-one between GS and GSF. No correlations were observed between patients carrying the different genotypes for Y54C or T400K and their mRNA levels for ABCG5 or ABCG8. The increased NPC1L1 and ACAT2 mRNA levels in gallstone patients might indicate an upregulated absorption and esterification of cholesterol in the small intestine.

[Expression and regulation of megalin in gallbladder mucosa associated with cholesterol gallstone disease].

OBJECTIVE: To explore the relationship between expression and regulation of Megalin in gallbladder mucosa and cholesterol gallstone disease. METHODS: Gallbladder mucosa, gallbladder wall, bile, gallstone were collected from 29 patients with cholesterol gallstone disease (GS) and 12 patients with gallstone free (GSF). Lipids of bile and stone were measured by kits. Expression of Megalin and Cubilin was analyzed by Real-time PCR. GBC-SD cell line were treated with T0901317, 9-cis retinoic acid, chenodeoxycholic acid (CDCA), the agonists of LXR, RXR, FXR, respectively. Gene expressions were detected. RESULTS: Biliary cholesterol % molar and CSI increased significantly in GS group [(7.98 +/- 0.44) mol% vs (4.87 +/- 0.39) mol%, P < 0.01]. Megalin expression in GS group was significantly higher than that in GSF group (P < 0.05) and cubilin expression was similar between two groups. In vitro experiments showed that CDCA markedly increased expression of megalin. CONCLUSION: This study shows that the increased expression Megalin may help to increase cholesterol uptake in gallbladder and play a compensative role in GS. FXR may participate in the transcription regulating of Megalin.

ATP binding cassette G8 T400K polymorphism may affect the risk of gallstone disease among Chinese males.

BACKGROUND: Supersaturation of bile with cholesterol is a primary step in the formation of cholesterol gallstones. ATP binding cassette (ABC) G5 and G8 play an important role in regulating sterol absorption and secretion. To investigate a possible association between transporter gene polymorphism and gallstone formation, we examined five common polymorphisms in the ABCG5 (Q604E) and ABCG8 (D19H, Y54C, T400K, A632V) genes in patients with gallstone disease (GS). METHODS: Study subjects included 287 patients with GS and 219 gallstone free controls (GSF). Polymorphisms were determined using PCR-RFLP analysis or the Taqman MGB assay. Plasma and biliary lipid levels were measured. RESULTS: 2 SNPs of ABCG8 gene (Y54C and T400K) showed strong linkage disequilibrium (D'=0.824, r2=0.579). Male carriers of the less frequent K allele of ABCG8 T400K had a 2.31-fold elevated risk [95% confidence interval (CI) 1.12 approximately 4.76, P=0.023] for gallstone disease compared to male with the common genotype after the adjustment for age, body mass index. Males with the K allele had lower plasma triglyceride (P=0.044) and biliary phospholipid (P=0.035) levels than TT homozygotes. No such association was found in female or other 4 SNPs. CONCLUSIONS: These findings indicate that the T400K polymorphism in ABCG8 may be associated with the incidence of gallstone disease in males.

Estrogen receptor beta mediates hepatotoxicity induced by perfluorooctane sulfonate in mouse.

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.

Association of polycyclic aromatic hydrocarbons and asthma among children 6-19 years: NHANES 2001-2008 and NHANES 2011-2012.

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.

Organochloride pesticides induced hepatic ABCG5/G8 expression and lipogenesis in Chinese patients with gallstone disease.

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.

The NPC1L1 Polymorphism 1679C>G Is Associated with Gallstone Disease in Chinese Patients.

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.