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1.
Ann Rheum Dis ; 78(10): 1430-1437, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31289104

RESUMO

OBJECTIVE: The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. METHODS: We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). RESULTS: This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10- 8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three 'gout vs AHUA GWAS'-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level. CONCLUSIONS: This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.

2.
Sleep ; 42(6)2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-30810208

RESUMO

Usual sleep duration has substantial heritability and is associated with various physical and psychiatric conditions as well as mortality. However, for its genetic locus, only PAX8 and VRK2 have been replicated in previous genome-wide association studies (GWAS). We conducted a GWAS meta-analysis of self-reported usual sleep duration using three population-based cohorts totaling 31 230 Japanese individuals. A genome-wide significant locus was identified at 12q24 (p-value < 5.0 × 10-8). Subsequently, a functional variant in the ALDH2 locus, rs671, was replicated in an independent sample of 5140 Japanese individuals (p-value = 0.004). The association signal, however, disappeared after adjusting for alcohol consumption, indicating the possibility that the rs671 genotype modifies sleep duration via alcohol consumption. This hypothesis explained a modest genetic correlation observed between sleep duration and alcohol consumption (rG = 0.23). A Mendelian randomization analysis using rs671 and other variants as instrumental variables confirmed this by showing a causal effect of alcohol consumption, but not of coffee consumption on sleep duration. Another genome-wide significant locus was identified at 5q33 after adjusting for drinking frequency. However, this locus was not replicated, nor was the PAX8 and VRK2. Our study has confirmed that a functional ALDH2 variant, rs671, most strongly influences on usual sleep duration possibly via alcohol consumption in the Japanese population, and presumably in East Asian populations. This highlights the importance of considering the involvement of alcohol consumption in future GWAS of usual sleep duration, even in non-East Asian populations, where rs671 is monomorphic.

3.
Med Sci Sports Exerc ; 50(12): 2433-2441, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30102679

RESUMO

PURPOSE: Although several genetic factors may play a role in leisure-time exercise behavior, there is currently no evidence of a significant genomewide association, and candidate gene replication studies have produced inconsistent results. METHODS: We conducted a two-stage genomewide association study and candidate single-nucleotide polymorphisms (SNP) association study on leisure-time exercise behavior using 13,980 discovery samples from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study, and 2036 replication samples from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center-2 study. Leisure-time physical activity was measured using a self-administered questionnaire that inquired about the type, frequency and duration of exercise. Participants with ≥4 MET·h·wk of leisure-time physical activity were defined as exhibiting leisure-time exercise behavior. Association testing using mixed linear regression models was performed on the discovery and replication samples, after which the results were combined in a meta-analysis. In addition, we tested six candidate genetic variants derived from previous genomewide association study. RESULTS: We found that one novel SNP (rs10252228) located in the intergenic region between NPSR1 and DPY19L1 was significantly associated with leisure-time exercise behavior in discovery samples. This association was also significant in replication samples (combined P value by meta-analysis = 2.2 × 10). Several SNP linked with rs10252228 were significantly associated with gene expression of DPY19L1 and DP19L2P1 in skeletal muscle, heart, whole blood, and the nervous system. Among the candidate SNP, rs12612420 in DNAPTP6 demonstrated nominal significance in discovery samples but not in replication samples. CONCLUSIONS: We identified a novel genetic variant associated with regular leisure-time exercise behavior. Further functional studies are required to validate the role of these variants in exercise behavior.

4.
Am J Nephrol ; 47(5): 304-316, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29779033

RESUMO

BACKGROUND: Chronic kidney disease (CKD) is a rapidly growing, worldwide public health problem. Recent advances in genome-wide-association studies (GWAS) revealed several genetic loci associated with renal function traits worldwide. METHODS: We investigated the association of genetic factors with the levels of serum creatinine (SCr) and the estimated glomerular filtration rate (eGFR) in Japanese population-based cohorts analyzing the GWAS imputed data with 11,221 subjects and 12,617,569 variants, and replicated the findings with the 148,829 hospital-based Japanese subjects. RESULTS: In the discovery phase, 28 variants within 4 loci (chromosome [chr] 2 with 8 variants including rs3770636 in the LDL receptor related protein 2 gene locus, on chr 5 with 2 variants including rs270184, chr 17 with 15 variants including rs3785837 in the BCAS3 gene locus, and chr 18 with 3 variants including rs74183647 in the nuclear factor of -activated T-cells 1 gene locus) reached the suggestive level of p < 1 × 10-6 in association with eGFR and SCr, and 2 variants on chr 4 (including rs78351985 in the microsomal triglyceride transfer protein gene locus) fulfilled the suggestive level in association with the risk of CKD. In the replication phase, 25 variants within 3 loci (chr 2 with 7 variants, chr 17 with 15 variants and chr 18 with 3 variants) in association with eGFR and SCr, and 2 variants on chr 4 associated with the risk of CKD became nominally statistically significant after Bonferroni correction, among which 15 variants on chr 17 and 3 variants on chr 18 reached genome-wide significance of p < 5 × 10-8 in the combined study meta-analysis. The associations of the loci on chr 2 and 18 with eGFR and SCr as well as that on chr 4 with CKD risk have not been previously reported in the Japanese and East Asian populations. CONCLUSION: Although the present GWAS of renal function traits included the largest sample of Japanese participants to date, we did not identify novel loci for renal traits. However, we identified the novel associations of the genetic loci on chr 2, 4, and 18 with renal function traits in the Japanese population, suggesting these are transethnic loci. Further investigations of these associations are expected to further validate our findings for the potential establishment of personalized prevention of renal disease in the Japanese and East Asian populations.

5.
Sci Rep ; 8(1): 1493, 2018 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-29367735

RESUMO

Coffee is one of the most widely consumed beverages worldwide, and its role in human health has received much attention. Although genome-wide association studies (GWASs) have investigated genetic variants associated with coffee consumption in European populations, no such study has yet been conducted in an Asian population. Here, we conducted a GWAS to identify common genetic variations that affected coffee consumption in a Japanese population of 11,261 participants recruited as a part of the Japan Multi-Institutional Collaborative Cohort (J-MICC) study. Coffee consumption was collected using a self-administered questionnaire, and converted from categories to cups/day. In the discovery stage (n = 6,312), we found 2 independent loci (12q24.12-13 and 5q33.3) that met suggestive significance (P < 1 × 10-6). In the replication stage (n = 4,949), the lead variant for the 12q24.12-13 locus (rs2074356) was significantly associated with habitual coffee consumption (P = 2.2 × 10-6), whereas the lead variant for the 5q33.3 locus (rs1957553) was not (P = 0.53). A meta-analysis of the discovery and replication populations, and the combined analysis using all subjects, revealed that rs2074356 achieved genome-wide significance (P = 2.2 × 10-16 for a meta-analysis). These findings indicate that the 12q24.12-13 locus is associated with coffee consumption among a Japanese population.

6.
J Atheroscler Thromb ; 24(12): 1267-1281, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28904253

RESUMO

AIM: Stroke is associated closely with vascular homeostasis, and several complex processes and interacting pathways, which involve various genetic and environmental factors, contribute to the risk of stroke. Although adrenomedullin (ADM) has a number of physiological and vasoprotective functions, there are few studies of the ADM receptor system in humans. The ADM receptor comprises a calcitonin-receptor-like receptor (CLR) and receptor activity-modifying proteins (RAMPs). We analyzed single nucleotide polymorphisms (SNPs) in the RAMP2 and CLR genes to determine their association with stroke in the light of gene-environment interactions. METHODS: Using cross-sectional data from the Japan Multi-Institutional Collaborative Cohort Study in the baseline surveys, 14,087 participants from 12 research areas were genotyped. We conducted a hypothesis-based association between stroke prevalence and SNPs in the RAMP2 and CLR genes based on data abstracted from two SNPs in RAMP2 and 369 SNPs in CLR. We selected five SNPs from among the CLR variants (rs77035639, rs3815524, rs75380157, rs574603859, and rs147565266) and one RAMP2 SNP (rs753152), which were associated with stroke, for analysis. RESULTS: Five of the SNPs (rs77035639, rs3815524, rs75380157, rs147565266, and rs753152) showed no significant association with obesity, ischemic heart disease, hypertension, dyslipidemia, and diabetes. In the logistic regression analysis, rs574603859 had a lower odds ratio (0.238; 95% confidence interval, 0.076-0.745, adjusted for age, sex, and research area) and the other SNPs had higher odds ratios for association with stroke. CONCLUSIONS: This was the first study to investigate the relationships between ADM receptor genes (RAMP2 and CLR) and stroke in the light of gene-environment interactions in human.


Assuntos
Biomarcadores/metabolismo , Proteína Semelhante a Receptor de Calcitonina/genética , Polimorfismo de Nucleotídeo Único , Proteína 2 Modificadora da Atividade de Receptores/genética , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Estudos de Coortes , Estudos Transversais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
7.
J Epidemiol ; 27(9): 420-427, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28576445

RESUMO

BACKGROUND: An increased risk of total death owing to human T-lymphotropic virus type-I (HTLV-I) infection has been reported. However, its etiology and protective factors are unclear. Various studies reported fluctuations in immune-inflammatory status among HTLV-I carriers. We conducted a matched cohort study among the general population in an HTLV-I-endemic region of Japan to investigate the interaction between inflammatory gene polymorphisms and HTLV-I infection for total death, incidence of cancer, and atherosclerosis-related diseases. METHOD: We selected 2180 sub-cohort subjects aged 35-69 years from the cohort population, after matching for age, sex, and region with HTLV-I seropositives. They were followed up for a maximum of 10 years. Inflammatory gene polymorphisms were selected from TNF-α, IL-10, and NF-κB1. A Cox proportional hazard model was used to estimate the hazard ratio (HR) and the interaction between gene polymorphisms and HTLV-I for risk of total death and incidence of cancer and atherosclerosis-related diseases. RESULTS: HTLV-I seropositivity rate was 6.4% in the cohort population. The interaction between TNF-α 1031T/C and HTLV-I for atherosclerosis-related disease incidence was statistically significant (p = 0.020). No significant interaction was observed between IL-10 819T/C or NF-κB1 94ATTG ins/del and HTLV-I. An increased HR for total death was observed in the Amami island region, after adjustment of various factors with gene polymorphisms (HR 3.03; 95% confidence interval, 1.18-7.77). CONCLUSION: The present study found the interaction between TNF-α 1031T/C and HTLV-I to be a risk factor for atherosclerosis-related disease. Further follow-up is warranted to investigate protective factors against developing diseases among susceptible HTLV-I carriers.

8.
PLoS One ; 12(4): e0174913, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28403148

RESUMO

BACKGROUND AND AIMS: Neutrophil infiltration of the liver is a typical feature of alcoholic liver injury. Human neutrophil peptide (HNP)-1 is an antimicrobial peptide secreted by neutrophils. The aim of this study was to determine if HNP-1 affects ethanol-induced liver injury and to examine the mechanism of liver injury induced by HNP-1. METHODS: Transgenic (TG) mice expressing HNP-1 under the control of a ß-actin-based promoter were established. Ethanol was orally administered to HNP-1 TG or wild-type C57BL/6N (WT) mice. SK-Hep1 hepatocellular carcinoma cells were used to investigate the effect of HNP-1 on hepatocytes in vitro. RESULTS: After 24 weeks of ethanol intake, hepatic fibrosis and hepatocyte apoptosis were significantly more severe in TG mice than in WT mice. Levels of CD14, TLR4, and IL-6 in liver tissues were higher in TG mice than in WT mice. Apoptosis was accompanied by higher protein levels of caspase-3, caspase-8, and cleaved PARP in liver tissue. In addition, phosphorylated ASK1, ASK1, phosphorylated JNK, JNK1, JNK2, Bax, Bak and Bim were all more abundant in TG mice than in WT mice. In contrast, the level of anti-apoptotic Bcl2 in the liver was significantly lower in TG mice than in WT mice. Analysis of microRNAs in liver tissue showed that miR-34a-5p expression was significantly higher in TG mice than in WT mice. Furthermore, in the presence of ethanol, HNP-1 increased the apoptosis with the decreased level of Bcl2 in a concentration-dependent manner in vitro. CONCLUSIONS: HNP-1 secreted by neutrophils may exacerbate alcohol-induced hepatic fibrosis and hepatocyte apoptosis with a decrease in Bcl2 expression and an increase in miR-34a-5p expression.


Assuntos
Apoptose , Etanol/toxicidade , Hepatócitos/fisiologia , alfa-Defensinas/fisiologia , Animais , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático , Hepatócitos/efeitos dos fármacos , Humanos , Cirrose Hepática Alcoólica , Masculino , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/metabolismo , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
9.
Mol Med Rep ; 14(6): 5385-5394, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27779710

RESUMO

Metabolic syndrome based on insulin resistance (IR) and hypertension is a risk factor for advanced liver disease and cardiovascular disease in patients with nonalcoholic steatohepatitis (NASH). The present study investigated the effects of severe hypertension induced by a high­salt (HS) diet and antihypertensive therapy on the pathophysiological condition of spontaneously hypertensive rats (SHRs) with steatohepatitis. Steatohepatitis was induced using a choline-deficient, L-amino acid-defined diet (CDAA). Male SHRs (7­week­old) were randomly divided into five groups: Those receiving 6 weeks of standard chow with a normal salt concentration, followed by an additional 8 weeks of standard chow or CDAA with a normal salt concentration (control and CDAA groups, respectively); and those receiving 6 weeks of standard chow with HS, followed by CDAA with HS for an additional 8 weeks, with or without the antihypertensive agents, amlodipine (Aml) or hydralazine. In the CDAA and CDAA+HS groups, blood pressure was significantly correlated with serum levels of insulin, fasting blood glucose and homeostasis model assessment (HOMA)­IR. Antihypertensive therapy ameliorated the elevated glucose, insulin and HOMA­IR. Furthermore, the increased levels of serum interleukin (IL)­6 following the CDAA+HS diet were attenuated by antihypertensive therapy. The serum levels of IL­10 were increased by antihypertensive therapy, and the decrease in the proportion of splenic CD4+CD25+forkhead box P3+ T cells observed following the CDAA+HS diet tended to be restored by Aml. In conclusion, antihypertensive therapy improved glucose metabolism and imbalances in cytokine expression in the rat model of hypertension with steatohepatitis, suggesting that antihypertensive therapy acting through immunological factors may be beneficial for patients with metabolic syndrome-associated NASH.


Assuntos
Anti-Hipertensivos/farmacologia , Resistência à Insulina , Interleucina-10/sangue , Interleucina-6/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Biomarcadores , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Dieta , Modelos Animais de Doenças , Hipertensão/complicações , Hipertensão/fisiopatologia , Insulina/sangue , Insulina/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Ratos , Ratos Endogâmicos SHR , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
10.
Prev Med Rep ; 3: 288-95, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27419029

RESUMO

OBJECTIVE: Inflammation is closely involved in the development of type 2 diabetes, and cigarette smoking acts as potent inducer of inflammation. We therefore investigated interactions between inflammation-related gene polymorphisms and cigarette smoking on glycated hemoglobin (HbA1c) in the Japanese general population. METHOD: We conducted a cross-sectional study using data collected from 2619 Japanese (1274 males and 1345 females) 40-69 years of age who participated in baseline survey of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study (2005-2008). Eight polymorphisms in seven genes (interleukin [IL]-1ß, IL-2, IL-4, IL-8, IL-10, IL-13 and tumor necrosis factor-α) were determined using the Invader assay. The interactions of smoking and gene polymorphisms on HbA1c levels were analyzed using multiple linear and logistic regression models and analysis of covariance with adjustment for potential confounders. RESULTS: Among the eight polymorphisms, only one significant interaction was detected for IL-1ß T-31C (P < 0.0001). Among the subjects carrying TT genotype, current heavy smokers (≥ 20 cigarettes/day) had higher HbA1c (5.83 [95% confidence interval 5.67-5.99] %) versus all other smoking status groups (never 5.49 [5.41-5.56] %, former 5.54 [5.43-5.65] %, current moderate [< 20 cigarettes/day] 5.50 [5.30-5.69] %), whereas such differences were not observed in the subjects with C allele. The logistic regression analyses regarding high-normal HbA1c levels showed a similar pattern of results. CONCLUSION: Smoking status did not interact with any other inflammation-related polymorphisms except for IL-1ß T-31C. Heavy smokers harboring the TT genotype of IL-1ß T-31C polymorphism show a greater adverse effect of smoking on HbA1c levels among Japanese middle-aged subjects.

11.
J Atheroscler Thromb ; 23(6): 681-91, 2016 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-26797265

RESUMO

AIM: Observational studies have reported that elevated homocysteine (Hcy) levels are associated with the risk of cardiovascular disease (CVD). However, interventions that lower Hcy do not provide a corresponding risk reduction. Therefore, the causal role of Hcy in CVD remains unclear. This 5-year prospective study investigated the associations of Hcy levels, folate intake, and host factors with arterial stiffness among the general Japanese population. METHODS: We prospectively recruited 658 participants (40-69 years old) from the general population during regular health checkup examinations. Arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI) at baseline and the 5-year follow-up. Folate intake was estimated using a structured questionnaire. Genotyping was used to evaluate the MTHFR C677T and MS A2756G gene polymorphisms. Ultrafast liquid chromatography was used to measure total plasma Hcy levels. Association between these variables and CAVI values was evaluated using general linear regression and logistic regression models that were adjusted for atherosclerosis-related factors. RESULTS: Men had higher Hcy levels and CAVI values and lower folate intake than women (all, p<0.001). At baseline, Hcy, folate intake, and the two genotypes were not associated with CAVI values for both sexes. Among men, Hcy levels were positively associated with CAVI values at the 5-year follow-up (p=0.033). Folate intake and the two genotypes were not associated with the 5-year CAVI values. CONCLUSION: Plasma Hcy may be involved in arterial stiffness progression, as monitored using CAVI, among men.


Assuntos
Tornozelo/irrigação sanguínea , Aterosclerose/diagnóstico , Doenças Cardiovasculares/diagnóstico , Homocisteína/sangue , Rigidez Vascular/fisiologia , Tornozelo/fisiopatologia , Aterosclerose/sangue , Aterosclerose/epidemiologia , Biomarcadores/sangue , Pressão Sanguínea , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Feminino , Genótipo , Humanos , Japão/epidemiologia , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Estudos Prospectivos , Fatores de Risco
12.
Diabetes Res Clin Pract ; 110(3): 301-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26497775

RESUMO

AIMS: Brain-muscle-Arnt-like protein-1 (BMAL1) and BMAL2 genes are essential components of the circadian clock, and are considered to be involved in glucose homeostasis. We examined whether single nucleotide polymorphisms (SNPs) of BMAL1 and BMAL2 were associated with the prevalence of type 2 diabetes (T2DM) in the general Japanese population. METHODS: We studied 2467 subjects (1232 men and 1235 women, 35-69 years old), including 105 men and 57 women with T2DM, from the participants of the Japan Multi-institutional Collaborative Cohort Study. The association between SNPs in the BMAL1 (rs11022775 and rs2290035) and BMAL2 (rs7958822) genes and T2DM were analyzed by multiple logistic regression after adjustment for potential confounders. Analysis was also performed after stratification by body mass index (≥25 kg/m(2) and <25 kg/m(2)) to investigate an interaction between genotypes and obesity. RESULTS: The A/G and A/A genotypes of BMAL2 rs7958822 showed significantly higher adjusted odds ratios (OR) for T2DM than the G/G genotype among obese men (OR=2.2, 95% confidence intervals [CI] 1.1, 4.6, P for interaction=0.0495) and obese women (OR=2.7, 95% CI 1.1, 6.7, P for interaction=0.199). There were no significant associations between BMAL1 rs11022775 or rs2290035 genotypes and T2DM. CONCLUSIONS: To the best of our knowledge, this is the first study to show the significant association between BMAL2 rs7958822 genotype and T2DM among obese subjects.


Assuntos
Fatores de Transcrição ARNTL/genética , Diabetes Mellitus Tipo 2/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Índice de Massa Corporal , Estudos de Coortes , Estudos Transversais , Feminino , Interação Gene-Ambiente , Genótipo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prevalência
13.
Oncol Rep ; 33(4): 1657-66, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25607821

RESUMO

The molecular mechanisms underlying the progression of nonalcoholic steatohepatitis (NASH) have not been fully elucidated. The aim of this study was to identify factors involved in NASH progression by analysis of pathophysiological features and gene-expression profiles in livers of STAM mice, a model of NASH-associated hepatocarcinogenesis. C57BL/6N (B6N) mice were injected with streptozotocin to generate STAM mice. Four-week-old male STAM and B6N mice were fed a high-fat diet (HFD) (STAM-F, B6N-F) or a conventional diet (STAM-C, B6N-C) until they were 10, 14, or 18 weeks old. Blood glucose and nonalcoholic fatty liver disease (NAFLD) activity scores of STAM-F were higher than those of STAM-C during all observation periods. STAM-F mice had more severe hepatic fibrosis at 14 weeks, and exhibited higher levels of α-fetoprotein-positive hepatic tumor formation with multiplication than STAM-C mice at 18 weeks. At 14 weeks, cDNA microarray analysis revealed that the hepatic expression of eight mRNAs was ≥30-fold higher in STAM-F than B6N-F mice. The expression of another four genes was increased ≥5-fold in STAM-F than B6N-F mice, and ≥5-fold in B6N-F relative to B6N-C mice. Of the 12 genes, the difference in Sptlc3 mRNA expression was most pronounced, and gradually increased over time, as determined by quantitative RT-PCR in STAM-F mice. In addition, Sptlc3 mRNA expression in STAM-F mice was higher than that in db/db mice that received HFD and in B6N mice fed a choline­deficient L-amino acid (CDAA)-defined diet. In conclusion, a high-fat diet aggravated pathophysiological findings in the liver in NASH mouse models, and the hepatic expression of Sptlc3 mRNA was potentially associated with NASH progression.


Assuntos
Neoplasias Hepáticas Experimentais/etiologia , Fígado/enzimologia , Hepatopatia Gordurosa não Alcoólica/complicações , Serina C-Palmitoiltransferase/biossíntese , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Deficiência de Colina/complicações , Cocarcinogênese , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/genética , Dieta Hiperlipídica/efeitos adversos , Progressão da Doença , Perfilação da Expressão Gênica , Hiperglicemia/complicações , Hiperglicemia/enzimologia , Hiperinsulinismo/complicações , Hiperinsulinismo/enzimologia , Fígado/patologia , Cirrose Hepática/enzimologia , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Neoplasias Hepáticas Experimentais/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/patologia , Lesões Pré-Cancerosas/complicações , Lesões Pré-Cancerosas/enzimologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores para Leptina/deficiência , Serina C-Palmitoiltransferase/genética , Estreptozocina , alfa-Fetoproteínas/análise
14.
Int J Mol Med ; 33(1): 68-76, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24190226

RESUMO

The effect of hypertension on non-alcoholic fatty liver disease (NAFLD) remains unclear at the molecular level. In this study, we investigated the effects of hypertension on the degree of hepatic steatosis, liver injury and hepatic fibrosis induced by a choline-deficient L-amino acid-defined (CDAA) diet in spontaneously hypertensive rats (SHRs). Seven-week-old male SHRs were fed standard chow with high or normal salt concentrations for 7 weeks, followed by a CDAA diet containing high or normal salt for an additional 8 or 24 weeks. Hepatic steatosis was assessed using hepatic triglyceride levels and Oil red O staining. Hepatic fibrosis was evaluated using Sirius red and Azan staining. Systolic blood pressure (SBP) gradually increased with a high-salt diet and was significantly higher after 7 weeks of feeding with high-salt vs. normal-salt chow. After 8 weeks on the CDAA diet, the degree of hepatic steatosis did not differ between the high-salt and normal-salt groups; however, alanine aminotransferase and fasting blood glucose levels were significantly higher and hepatic mRNA levels for interleukin (IL)-10 and heme oxygenase (HO)-1 were significantly lower in the high-salt group compared with the normal-salt group. After 24 weeks on the CDAA diet, the high-salt group had significantly more severe hepatic fibrosis and a higher hepatic mRNA expression of α-smooth muscle actin and lower hepatic IL-10 and HO-1 mRNA levels compared with the normal-salt group. In conclusion, our results indicate that hypertension is a potential risk factor for liver injury and hepatic fibrosis through glucose intolerance and decreased IL-10-mediated or HO-1-induced anti-inflammatory mechanisms.


Assuntos
Deficiência de Colina/fisiopatologia , Dieta , Fígado Gorduroso/fisiopatologia , Hipertensão/fisiopatologia , Cirrose Hepática/fisiopatologia , Alanina Transaminase/sangue , Animais , Glicemia , Pressão Sanguínea , Fígado Gorduroso/complicações , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Hipertensão/complicações , Interleucina-10/genética , Interleucina-10/metabolismo , Fígado/metabolismo , Fígado/fisiopatologia , Cirrose Hepática/complicações , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos SHR , Fatores de Risco
15.
Eur J Med Res ; 18: 54, 2013 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-24321741

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a risk for hepatocellular carcinoma (HCC), but the association between a high-fructose diet and HCC is not fully understood. In this study, we investigated whether a high-fructose diet affects hepatocarcinogenesis induced by administration of diethylnitrosamine (DEN). METHODS: Seven-week-old male Sprague-Dawley rats were fed standard chow (controls), a high-fat diet (54% fat), or a high-fructose diet (66% fructose) for 8 weeks. All rats were given DEN at 50 µg/L in drinking water during the same period. Precancerous hepatocytes were detected by immunostaining of the placental form of glutathione-S-transferase (GST-P). The number of GST-P-positive hepatocytes was assessed in liver specimens. RESULTS: Serum levels of total cholesterol were similar among the three groups, but serum triglyceride, fasting blood glucose, and insulin levels were higher in the high-fructose group compared to the high-fat group. In contrast, hepatic steatosis was more severe in the high-fat group compared with the high-fructose and control groups, but the incidence of GST-P-positive specimens was significantly higher in the high-fructose group compared to the other two groups. The average number of GST-P-positive hepatocytes in GST-P positive specimens in the high-fructose group was also higher than those in the other two groups. This high prevalence of GST-P-positive hepatocytes was accompanied by higher levels of 8-hydroxydeoxyguanosine in serum and liver tissue. CONCLUSIONS: These results indicate that dietary fructose, rather than dietary fat, increases the incidence of precancerous hepatocytes induced by administration of DEN via insulin resistance and oxidative stress in rat. Thus, excessive fructose intake may be a potential risk factor for hepatocarcinogenesis.


Assuntos
Carboidratos da Dieta/administração & dosagem , Carboidratos da Dieta/farmacologia , Frutose/administração & dosagem , Frutose/farmacologia , Hepatócitos/patologia , Lesões Pré-Cancerosas/patologia , Administração Oral , Animais , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Desoxiguanosina/análogos & derivados , Desoxiguanosina/sangue , Dieta Hiperlipídica , Dietilnitrosamina/administração & dosagem , Dietilnitrosamina/farmacologia , Fígado Gorduroso/sangue , Fígado Gorduroso/enzimologia , Fígado Gorduroso/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa Transferase/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Incidência , Masculino , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Lesões Pré-Cancerosas/sangue , Lesões Pré-Cancerosas/enzimologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
16.
Liver Int ; 33(10): 1549-56, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23682724

RESUMO

BACKGROUND: Neutrophils infiltrate the livers of patients with nonalcoholic steatohepatitis (NASH). Human neutrophil peptides (HNPs) induce cytokine and chemokine production under inflammatory conditions, which may contribute to the progression of NASH. In this study, we focused on the effects of HNP-1 on hepatic steatosis and fibrosis in a mouse model of NASH induced by a choline-deficient, L-amino acid-defined (CDAA) diet. MATERIALS & METHODS: We generated transgenic mice expressing HNP-1 under the control of a ß-actin-based promoter. HNP-1 transgenic and wild-type C57BL/6N mice were fed a CDAA diet for 16 weeks to induce hepatic steatosis and fibrosis. Serological and histological features were examined, and the effects of HNP-1 on hepatic stellate cell lines were assessed. RESULTS: HNP-1 transgenic and wild-type mice fed the CDAA diet showed no significant differences in serum alanine aminotransferase levels or the degree of hepatic steatosis based on Oil red O staining and hepatic triglyceride content. In contrast, Sirius Red and Azan staining showed significantly more severe hepatic fibrosis in HNP-1 transgenic mice compared with wild-type mice. In addition, significantly more α-smooth muscle actin-positive hepatic stellate cells were observed in the transgenic mice than in the wild-type mice. Finally, the proliferation of the LI90 hepatic stellate cell line increased in response to HNP-1. CONCLUSION: Our data indicate that HNP-1 enhances hepatic fibrosis in fatty liver by inducing hepatic stellate cell proliferation. Thus, neutrophil-derived HNP-1 may contribute to the progression of NASH.


Assuntos
Dieta , Fígado Gorduroso/metabolismo , Cirrose Hepática/metabolismo , alfa-Defensinas/metabolismo , 2,2'-Dipiridil/análogos & derivados , Alanina Transaminase/sangue , Aminoácidos/metabolismo , Animais , Compostos Azabicíclicos , Compostos Azo , Proliferação de Células , Deficiência de Colina , Células Estreladas do Fígado/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Hepatopatia Gordurosa não Alcoólica
17.
Inflamm Bowel Dis ; 18(4): 667-75, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21928371

RESUMO

BACKGROUND: Human neutrophil peptide (HNP)-1, HNP-2, and HNP-3 (HNP-1-3) are useful biomarkers for ulcerative colitis (UC). The precise roles of these peptides in UC are poorly understood, however. The aim of this study was to determine whether HNP-1 affects disease activity in mice with experimental colitis. METHODS: Experimental colitis was induced in BALB/c or severe combined immunodeficiency (SCID) mice using dextran sulfate sodium (DSS). Mice were subsequently treated intraperitoneally with HNP-1 (100 µg/day) or phosphate-buffered saline (PBS) from day 4 to day 6. The severity of colitis was evaluated based on a disease activity index, histologic score, and cytokine expression. RESULTS: Body weight and colon length significantly decreased and the disease activity index score, histologic score, and myeloperoxidase activity significantly increased in HNP-1-treated BALB/c mice compared with PBS-treated mice. Interferon-γ and tumor necrosis factor-α levels in colon culture supernatants-derived HNP-1-treated mice were also significantly higher, and interleukin (IL)-1ß levels tended to increase in response to HNP-1. In addition, treating SCID mice with HNP-1 aggravated DSS-induced colitis and IL-1ß levels in colon culture supernatants from these mice were significantly higher than in cultures obtained from control mice. Furthermore, in both BALB/c and SCID mice increased recruitment of F4/80-positive macrophages was observed in the inflamed colonic mucosa following HNP-1 injections. CONCLUSIONS: High concentrations of HNP-1 aggravate DSS-induced colitis, including upregulated expression of such macrophage-derived cytokines as IL-1ß. These results indicate that high concentrations of HNP-1-3 in patients with UC may exacerbate disease activity via increased cytokine production.


Assuntos
Colite/metabolismo , Colo/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , alfa-Defensinas/efeitos adversos , Animais , Células Cultivadas , Colite/induzido quimicamente , Colite/patologia , Colo/anatomia & histologia , Colo/metabolismo , Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Humanos , Interferon gama/metabolismo , Interleucina-1beta/biossíntese , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Peroxidase/análise , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
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