Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dipeptidyl peptidase IV is a cell surface ectopeptidase with widespread tissue distribution. Recently it was shown to display extracellular matrix-binding properties; therefore its role in cirrhosis is of interest. The aim of this study was to use monoclonal antibodies directed against the human CD26 antigen (which has been shown to be dipeptidyl peptidase IV) to study the distribution of this molecule in normal human and cirrhotic liver. Identical staining was obtained with the three monoclonal antibodies (TaI, 1F7 and TS145) and enzyme histochemistry. In normal liver (n = 11) intense staining of hepatic acinar zones 2 and 3 was present, but little staining was seen in zone I. Hepatocyte staining was confined to the bile canalicular domain. In cirrhotic livers (n = 23) obtained at transplantation, staining of regenerating nodules without a zonal pattern was present. In addition, we saw staining of the lymphoid cell infiltrate and proliferating bile ductules. In a minority of cirrhotic biopsy specimens (four) staining of the basolateral hepatocyte domain in regenerating nodules was seen. Biopsy specimens from hepatic allografts (n = 28) were used as disease controls. These samples all showed preferential staining of zones 2 and 3, similar to that in normal biopsy specimens. Eleven of these samples showed staining of the basolateral and bile canalicular domains. In conclusion, the normal acinar distribution of dipeptidyl peptidase IV (zones 2 and 3) is lost in cirrhotic nodules. Furthermore, the altered membrane distribution of this molecule in cirrhosis and allograft rejection may allow increased hepatocyte extracellular matrix interactions during organ remodeling.
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PMID:Altered zonal expression of the CD26 antigen (dipeptidyl peptidase IV) in human cirrhotic liver. 135 May 63

The hallmarks of chronic liver diseases are chronic inflammation, cellular damage, regeneration and fibrosis. An appreciation of intrahepatic molecular expression patterns in normal and diseased liver provides clues for understanding pathogenic pathways whilst studies of the structure and function of molecules implicated in liver disease provide insights into their potential as therapeutic targets. We have examined the expression, function, molecular structure and structure-function relationships of type IV dipeptidyl aminopeptidases. In particular, the roles of CD26/DPPIV in T-cell proliferation and chemotaxis and of fibroblast activation protein in human cirrhosis are discussed. We have investigated the pathogenesis of liver disease by characterising patterns of cytokine and growth factor expression in experimental and human cirrhosis. We have quite recently expanded this approach to use differential gene expression analyses to elucidate overall pathways of gene activation and suppression in human cirrhosis. In addition, our detailed molecular and cellular studies of the mechanisms of spontaneous liver transplant tolerance have generated novel insights into this process. This review touches on these diverse aspects of liver function and disease.
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PMID:Molecular pathogenesis of liver disease: an approach to hepatic inflammation, cirrhosis and liver transplant tolerance. 1080 16

Fibroblast activation protein (FAPalpha) is a member of the cell surface dipeptidyl peptidase (DPP) family of serine proteases. In its dimer form, FAPalpha exhibits gelatinase, collagenase, and DPP activity in vitro. Reactive fibroblasts in healing wounds and stromal fibroblasts associated with epithelial tumors express FAPalpha. Idiopathic pulmonary fibrosis (IPF) is a disease of the lung characterized by progressive fibrosis with no clear etiology or molecular marker for disease activity. Recently, it has been shown that fibroblast FAPalpha expression is induced in liver cirrhosis, with an expression pattern distinct from alpha-smooth muscle actin (alpha-SMA). In this study, we determine whether FAPalpha expression is selectively induced in areas of ongoing tissue remodeling characterized by fibroblast foci in IPF. Human lung tissue was obtained from patients with IPF, centrilobular emphysema, and normal lung. Immunohistochemical studies were performed using anti-FAPalpha antibody and antibodies against alpha-SMA and CD26 (DPPIV), another member of the DPP family. We found that FAPalpha was not expressed in normal human lung tissue or tissue with evidence of centriacinar emphysema, but was induced in all patients with IPF and With a pattern distinct from that of CD26 found primarily on hyperplastic alveolar epithelium. Specifically, FAPalpha was detected in fibroblast foci and in fibrotic interstitium and not in the interstitium of adjacent architecturally normal lung. Alveolar/airway epithelium and vascular smooth muscle did not express FAPalpha. This is the first report of FAPalpha expression in IPF and our results suggest that FAPalpha is selectively induced in fibrotic foci, but not in normal or emphysematous lung. Future studies will address whether FAPalpha may be used as a marker for disease activity in IPF.
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PMID:Fibroblast activation protein: a serine protease expressed at the remodeling interface in idiopathic pulmonary fibrosis. 1661 31

Fibroblast activation protein (FAP) is a dipeptidyl peptidase (DPP) and endopeptidase that is weakly expressed in normal adult human tissues but is greatly up-regulated in activated mesenchymal cells of tumors and chronically injured tissue. The identities and locations of target substrates of FAP are poorly defined, in contrast to the related protease DPP4. This study is the first to characterize the physiological substrate repertoire of the DPP activity of endogenous FAP present in plasma. Four substrates, neuropeptide Y (NPY), peptide YY, B-type natriuretic peptide and substance P, were analyzed by mass spectrometry following proteolysis in human or mouse plasma, and by in vivo localization in human liver tissues with cirrhosis and hepatocellular carcinoma (HCC). NPY was the most efficiently cleaved substrate of both human and mouse FAP, whereas all four peptides were efficiently cleaved by endogenous DPP4, indicating that the in vivo degradomes of FAP and DPP4 differ. All detectable DPP-specific proteolysis and C-terminal processing of these neuropeptides was attributable to FAP and DPP4, and plasma kallikrein, respectively, highlighting their combined physiological significance in the regulation of these neuropeptides. In cirrhotic liver and HCC, NPY and its receptor Y2R, but not Y5R, were increased in hepatocytes near the parenchymal-stromal interface where there is an opportunity to interact with FAP expressed on nearby activated mesenchymal cells in the stroma. These novel findings provide insights into the substrate specificity of FAP, which differs greatly from DPP4, and reveal a potential function for FAP in neuropeptide regulation within liver and cancer biology.
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PMID:Neuropeptide Y is a physiological substrate of fibroblast activation protein: Enzyme kinetics in blood plasma and expression of Y2R and Y5R in human liver cirrhosis and hepatocellular carcinoma. 2662 86

Non-alcoholic fatty liver disease (NAFLD) represents one of the most common causes of chronic liver disease worldwide and is characterized by chronic liver inflammation and fibrosis leading to cirrhosis and increased risk of liver cancer in a proportion of patients. Effective anti-fibrotic agents have yet to be approved for the treatment of NAFLD. The present study aimed to evaluate the efficacy of dipeptidyl peptidase 4 inhibitors (DPP4-I) in the prevention of NAFLD progression in NAFLD patients with type 2 diabetes. The study was a single arm, multi-centre, non-randomised study of NAFLD patients with type 2 diabetes. NAFLD was diagnosed according to ultrasonographic findings. All the patients received 25 mg/day of alogliptin for 12 months. The efficacy of alogliptin in preventing NAFLD progression was assessed using overall NAFIC scores [non-alcoholic steatohepatitis (NASH), ferritin, insulin and type IV collagen 7S] and individual component scores according to baseline haemoglobin A1c (HbA1c) levels. Of the 39 patients enrolled in the study, 16 patients (40.3%) had NAFIC scores >2 points, indicating the presence of NASH. NAFIC scores markedly decreased following 12 months of alogliptin administration, but remained >2 points in 10 patients, indicating that NASH may have persisted in these patients. The relative risks for persistent NASH were 4.92 (95% confidence interval, 0.61-40.0) in the highest HbA1c tertile group compared with those in the lowest group. However, no statistically significant linear trend was observed across all HbA1c categories (P=0.145). DPP4-I may have efficacy against NAFLD progression in patients with type 2 diabetes with relatively lower HbA1c levels. DPP4-I may represent a potential new therapeutic strategy for the prevention of disease progression in NAFLD patients with type 2 diabetes.
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PMID:Efficacy of alogliptin in preventing non-alcoholic fatty liver disease progression in patients with type 2 diabetes. 2689 35

Non-alcoholic fatty liver disease (NAFLD) affects 25% of the population and can progress to cirrhosis with limited treatment options. As the liver secretes most of the blood plasma proteins, liver disease may affect the plasma proteome. Plasma proteome profiling of 48 patients with and without cirrhosis or NAFLD revealed six statistically significantly changing proteins (ALDOB, APOM, LGALS3BP, PIGR, VTN, and AFM), two of which are already linked to liver disease. Polymeric immunoglobulin receptor (PIGR) was significantly elevated in both cohorts by 170% in NAFLD and 298% in cirrhosis and was further validated in mouse models. Furthermore, a global correlation map of clinical and proteomic data strongly associated DPP4, ANPEP, TGFBI, PIGR, and APOE with NAFLD and cirrhosis. The prominent diabetic drug target DPP4 is an aminopeptidase like ANPEP, ENPEP, and LAP3, all of which are up-regulated in the human or mouse data. Furthermore, ANPEP and TGFBI have potential roles in extracellular matrix remodeling in fibrosis. Thus, plasma proteome profiling can identify potential biomarkers and drug targets in liver disease.
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PMID:Plasma proteome profiling discovers novel proteins associated with non-alcoholic fatty liver disease. 3082 64