ABSTRACT
OBJECTIVE: Progressive hepatic fibrosis can be considered the final stage of chronic liver disease. Hepatic stellate cells (HSC) play a central role in liver fibrogenesis. Thyroid hormones (TH, e.g. thyroxine; T4 and triiodothyronine; T3) significantly affect development, growth, cell differentiation and metabolism through activation of TH receptor α and/or ß (TRα/ß). Here, we evaluated the influence of TH in hepatic fibrogenesis. DESIGN: Human liver tissue was obtained from explanted livers following transplantation. TRα-deficient (TRα-KO) and wild-type (WT) mice were fed a control or a profibrogenic methionine-choline deficient (MCD) diet. Liver tissue was assessed by qRT-PCR for fibrogenic gene expression. In vitro, HSC were treated with TGFß in the presence or absence of T3. HSC with stable TRα knockdown and TRα deficient mouse embryonic fibroblasts (MEF) were used to determine receptor-specific function. Activation of HSC and MEF was assessed using the wound healing assay, Western blotting, and qRT-PCR. RESULTS: TRα and TRß expression is downregulated in the liver during hepatic fibrogenesis in humans and mice. TRα represents the dominant isoform in HSC. In vitro, T3 blunted TGFß-induced expression of fibrogenic genes in HSC and abrogated wound healing by modulating TGFß signalling, which depended on TRα presence. In vivo, TRα-KO enhanced MCD diet-induced liver fibrogenesis. CONCLUSION: These observations indicate that TH action in non-parenchymal cells is highly relevant. The interaction of TRα with TH regulates the phenotype of HSC via the TGFß signalling pathway. Thus, the TH-TR axis may be a valuable target for future therapy of liver fibrosis.
Subject(s)
Fibroblasts , Hepatic Stellate Cells , Animals , Mice , Humans , Hepatic Stellate Cells/metabolism , Thyroid Hormones/metabolism , Thyroid Hormones/pharmacology , Thyroid Hormone Receptors alpha/genetics , Thyroid Hormone Receptors alpha/metabolism , Transforming Growth Factor betaABSTRACT
Oxidative stress (OS) is an important pathophysiological mechanism in inflammatory bowel disease (IBD). However, clinical trials investigating compounds directly targeting OS in IBD yielded mixed results. The NRF2 (nuclear factor erythroid 2-related factor 2)/Keap1 (Kelch-like ECH-associated protein 1) pathway orchestrates cellular responses to OS, and dysregulation of this pathway has been implicated in IBD. Activation of the NRF2/Keap1 pathway may enhance antioxidant responses. Although this approach could help to attenuate OS and potentially improve clinical outcomes, an overview of human evidence for modulating the NRF2/Keap1 axis and more recent developments in IBD is lacking. This review explores the NRF2/Keap1 pathway as potential therapeutic target in IBD and presents compounds activating this pathway for future clinical applications.
Subject(s)
Inflammatory Bowel Diseases , NF-E2-Related Factor 2 , Humans , NF-E2-Related Factor 2/metabolism , Kelch-Like ECH-Associated Protein 1/metabolism , Oxidative Stress , Antioxidants/metabolism , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/etiologyABSTRACT
BACKGROUND: Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), are intestinal inflammatory disorders with a complex genetic background. Mice deficient for the runt-domain-transcription-factor3 (Runx3) develop spontaneous colitis. Human RUNX3 resides in an IBD-susceptibility locus. We studied the association of RUNX3 in a cohort of IBD patients and analyzed the interaction with SLC22A4/5. RUNX3 and OCTN1 mRNA expression was assessed in inflamed and noninflamed mucosa from patients and controls. METHODS: 543 IBD patients (309 CD / 234 UC) and 296 controls were included. Four single nucleotide polymorphisms (SNPs) and 4 microsatellite markers were studied for RUNX3. Five SNPs (including SNP-207G-->C and SNP1672C-->T) were analyzed for SLC22A4/5. RUNX3, and OCTN1 expression in mucosal tissue from 30 patients (14 UC / 16 CD) and 6 controls were determined by quantitative polymerase chain reaction. RESULTS: A significant association between RUNX3-SNP rs2236851 and UC (OR 1.61; 95% confidence interval [CI] 1.11-2.32, P = 0.020) was found. Carriership is associated with pancolitis (odds ratio [OR] 1.86; 95% CI 1.08-3.21). SLC22A4/5-SNPs rs272893 and rs273900 are associated with CD (OR 2.16; 95% CI 1.21-3.59 and OR 2.40; 95% CI 1.43-4.05). We found epistasis for carriership of a risk-associated allele in RUNX3 and SLC22A4/5 for UC patients versus CD patients (OR 3.83; 95% CI 1.26-11.67). RUNX3 mRNA expression is increased (P = 0.01) in inflamed colonic mucosa of UC patients compared to noninflamed mucosa and controls. CONCLUSIONS: We provide evidence for the genetic association of RUNX3 with UC and for CD with the IBD5 locus including SLC22A4/5. An epistatic effect of RUNX3 and SLC22A4 was associated with an increased risk for UC. Our data suggest a role for RUNX3 in UC susceptibility.
Subject(s)
Colitis, Ulcerative/genetics , Core Binding Factor Alpha 3 Subunit/genetics , Crohn Disease/genetics , Epistasis, Genetic/genetics , Organic Cation Transport Proteins/genetics , Adolescent , Adult , Aged , Case-Control Studies , Child , Chromosomes, Human, Pair 5 , Colitis, Ulcerative/metabolism , Colitis, Ulcerative/pathology , Colon/metabolism , Colon/pathology , Core Binding Factor Alpha 3 Subunit/metabolism , Crohn Disease/metabolism , Crohn Disease/pathology , Female , Genetic Predisposition to Disease , Genotype , Haplotypes , Humans , Immunoenzyme Techniques , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Male , Middle Aged , Nod2 Signaling Adaptor Protein/genetics , Organic Cation Transport Proteins/metabolism , Polymorphism, Single Nucleotide/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Solute Carrier Family 22 Member 5 , Symporters , Young AdultABSTRACT
OBJECTIVE: The multidrug resistance (MDR1) gene encodes for P-glycoprotein, a drug efflux pump. Mice deficient for the MDR1a gene spontaneously develop colitis. In humans, a polymorphism in exon 26 (C3435T) is associated with reduced expression levels and function of MDR1. Currently there are controversial data on the association between MDR1 and inflammatory bowel disease (IBD). The purpose of this study was to examine the involvement of this gene in IBD in a large population of Dutch patients with IBD and family-based controls. MATERIAL AND METHODS: A total of 781 IBD cases and 315 controls were investigated. CD phenotypes were determined according to the Vienna Classification. Individuals were genotyped for six single nucleotide polymorphisms (SNPs) close to and in the MDR1 locus. This included the C3435T variant and six microsatellite markers close to and in the MDR1 locus. Single locus association analysis, haplotype association analysis and haplotype sharing statistic (HSS) were used to search for differences between patients and controls. RESULTS: No association was observed for any of the SNPs with IBD as a group, or for ulcerative colitis, Crohn's disease and Crohn's disease phenotypes, either by single locus or haplotype association analysis or by HSS. CONCLUSIONS: No association was observed between the MDR1 gene and IBD. This suggests that it is unlikely that MDR1 plays a role in IBD susceptibility.
