ABSTRACT: Metabolic and bacterial phenotypes associated with inadequate ursodeoxycholic acid treatment response in patients with primary biliary cholangitis
Project description:We performed RNA sequencing of liver transcriptome from 12-week-old p40-/-IL-2Rα-/- (a mouse model of primary biliary cholangitis) and littermate p40-/-IL-2Ra+/- (control) mice.
Project description:Primary biliary cholangitis (PBC), formally known as primary biliary cirrhosis, is an autoimmune liver disease of unknown pathogenesis. Consequently, therapeutic targets for PBC have yet to be identified. As CD4+ T cells play a pivotal role in immunological dysfunction observed in PBC, we analyzed microRNA(miRNA) and mRNA expression in CD4+ T cells to investigate PBC pathogenesis and identify novel therapeutic targets.
Project description:Primary biliary cholangitis (PBC), formally known as primary biliary cirrhosis, is an autoimmune liver disease of unknown pathogenesis. Consequently, therapeutic targets for PBC have yet to be identified. As CD4+ T cells play a pivotal role in immunological dysfunction observed in PBC, we analyzed microRNA(miRNA) and mRNA expression in CD4+ T cells to investigate PBC pathogenesis and identify novel therapeutic targets.
Project description:Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and progressive fibrosis of the biliary tree. The bile acid receptor TGR5 is found on biliary epithelial cells (BECs), where it promotes secretion, proliferation and tight junction integrity. Thus, we speculated that changes in TGR5 expression in BECs may contribute to PSC pathogenesis.
Project description:Malignant transformation of adenomas of the duodenum is now the leading cause of death in familial adenomatous polyposis (FAP) patients who had a restorative proctocolectomy. Ursodeoxycholic acid (UDCA) modifies the biliary acid profile and could reduce the severity of duodenal adenomas and prevent such transformation.
Project description:Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), are heterogeneous chronic autoimmune diseases that may share underlying pathogenic mechanisms. Herein, we compared simultaneously analyzed blood transcriptomes from patients with PBC, PSC, and IBD.
Project description:Background: Glycyrrhizin, silymarin, and ursodeoxycholic acid are widely used hepatoprotectants for the treatment of liver disorders, such as hepatitis C virus infection, primary biliary cirrhosis, and hepatocellular carcinoma. Hypothesis/Purpose: However, few studies have evaluated the effects of these compounds on gene expression. Methods: Here, we used an oligonucleotide microarray approach to study the gene expression profile in human hepatoma cells treated with 25 μM of hepatoprotective agents. Results: Among a total of 30,968 genes, 252 genes were commonly regulated by all compounds. These compounds affected the expressions of genes involved in different biological pathways, such as neurotransmission and glucose and lipid metabolism. Genes involved in hepatocarcinogenesis, apoptosis, and anti-oxidative pathways were differentially regulated by all compounds. Moreover, interaction networks showed that nuclear factor-κB (NF-κB) might play a central role in the regulation of the gene expression network. Further analysis revealed that these hepatoprotectants inhibited NF-κB activation in a dose-dependent manner. Conclusion: Our data suggested that glycyrrhizin, silymarin, and ursodeoxycholic acid protected livers from damage by regulating the genes involved in apoptosis and oxidative stress. Moreover, the regulation of genes by hepatoprotectants might be through the suppression of NF-κB activities.
Project description:Background. Abcb4 (-/-) mice secrete phosphatidylcholine-deficient bile and develop sclerosing cholangitis (SC). The cholangitis involves differential hepatic transcription of genes whose products govern inflammation, activation of hepatic stellate cells and fibrosis. This study was undertaken to test the hypothesis that several genes involved in regulation of tissue inflammation and fibrosis display transcription rates that reflect SC disease activity. Methods. Abcb4 (-/-) mice fed cholic acid (CA) display high SC activity and ursodeoxycholic acid (UDCA) fed mice display low SC activity. Differential hepatic transcription of genes was accordingly measured in abcb4 (-/-) mice maintained on CA- and UDCA-supplemented diets using cDNA microarrays. Abcb4 (+/+) mice served as controls. The differential transcription of selected genes was verified by real time polymerase chain reaction. Liver tissue pathology was quantified by histopathology scoring and immunohistochemistry to visualize bile duct cells and activated hepatic stellate cells. Results. Differential transcription of Ccl2, Ccl20, Cxcl10, Nfκb1, Nfκb2, Tgfβ1, Tgfβ2, Sparc, Ctgf, Lgals3, Elf3, Spp1, Pdgfa, Pdgfrb, Col1a1, Col1a2 and Col4a1 genes paralleled the differing SC activities of cholic acid- and UDCA-fed abcb4 (-/-) mice. Histopathology scores and immunohistochemistry showed greatly enhanced activation of hepatic stellate cells during high SC activity due to CA feeding. Conclusion. Differential transcription of several genes relating to tissue inflammation and hepatic stellate cell activation parallels SC activity in abcb4 (-/-) mice. Data on their differential transcription may be used to gauge SC disease activity.
