Zur Kurzanzeige

Impact of UGT1A polymorphisms on inflammation and fibrogenesis in a humanized transgenic mouse model

dc.contributor.advisorStrassburg, Christian
dc.contributor.authorLanderer, Steffen
dc.date.accessioned2020-07-07T10:32:31Z
dc.date.available2021-07-07T22:00:19Z
dc.date.issued07.07.2020
dc.identifier.urihttps://hdl.handle.net/20.500.11811/8438
dc.description.abstractFibrogenesis represents a highly dynamic scarring response of the liver resulting from different causes of hepatic injury. A key process capable of activating a broad array of profibrogenic pathways is oxidative stress. Oxidative injury, induced by reactive oxygen species, is a strong inducer of hepatic stellate cell activation which represents a critical event in fibrogenesis. UDP-glucuronosyltransferase 1A (UGT1A) enzymes detoxify a broad range of endo- and xenobiotic compounds thereby contributing to antioxidative effects, modulation of inflammation and cytoprotection. By catalyzing the covalent binding of glucuronic acid to reactive metabolites or xenobiotics, UGT1As generate hydrophilic inactive glucuronides that are more easily eliminated from the body by biliary or renal excretion.
Regarding the role of hepatic glucuronidation for the development and avoidance of liver fibrosis only limited data are available. Therefore, the overall objective of the dissertation was to show that the presence of UGT1A polymorphisms leading to impaired transcriptional activation and lower enzymatic UGT1A activity results in aggravated fibrogenesis as a consequence of compromised UGT1A-mediated antioxidative tissue protection. To achieve this goal, fibrosis development was assessed during different models of hepatic injury in humanized transgenic (htg) UGT1A-WT and htgUGT1A-SNP mice (containing a human haplotype of 10 common occurring UGT1A SNPs). The following studies show a considerable effect of UGT1A gene products on fibrosis development and progression, which is found to be dependent on the etiology of liver damage. While lower hepatic UGT1A expression levels correlated with a higher degree of liver fibrosis during bile duct ligation (BDL)-induced obstructive cholestasis, reduced fibrogenesis and hence a protective effect of the low-function SNP variant was observed during hepatic steatosis/steatohepatitis evoked in the experimental setting of high-fat diet-induced liver injury.
Coffee consumption is epidemiologically associated with a lower risk of fibrosis progression in humans, and has previously been shown to be a potent inducer of UGT1A gene expression. During BDL, coffee administration increased transcriptional UGT1A activation in both mouse lines accompanied by a significant reduction of liver fibrosis. Moreover, a more pronounced downregulation of fibrosis-related marker genes as well as a potent reduction of oxidative liver injury was detected in htgUGT1A-WT animals. Therefore, a common UGT1A SNP haplotype observed in 10% of the white population, is suggested to represent a considerable risk factor for fibrosis progression in cholestasis-related disease, and could, in part, be functionally compensated by the inductive effects associated with coffee consumption. As a consequence, the beneficial effects of coffee could serve as a potential medical strategy for therapeutically activating UGT1A transcription in the clinical situation of cholestasis. This is the first study experimentally reporting a protective effect of this low-function Gilbert syndrome-associated haplotype leading to milder hepatic steatosis during the development of non-alcoholic steatohepatitis. Although a higher expression of UGT1A enzymes was observed in htgUGT1A-WT mice, htgUGT1A-SNP mice showed lower serum aminotransferase levels, reduced hepatic fat deposition and less fibrosis. The data from these experiments therefore contributes to a better understanding of one of the fastest growing hepatic disorders worldwide by identifying a novel role of UGT1A enzymes during the development of hepatic steatosis.
In addition to the antifibrotic effects, coffee intake has further been associated with a reduced risk of hepatocellular carcinoma (HCC) and cirrhosis, a major risk factor for the development of liver cancer in humans. The inadequate processing of carcinogenic xenobiotics, as a consequence of low-activity UGT1A variants, has previously been suggested to contribute or to initiate the process of liver carcinogenesis. Until now, experimental evidence for the evaluation of several case-control studies supporting this hypothesis is missing. This thesis provides experimental data for the protective influence of UGT1A proteins against neoplastic transformation chemically-induced by diethylnitrosamine (DEN). HtgUGT1A-SNP mice, which presumably show a reduced capacity of environmental carcinogen detoxification, exhibit markedly increased nodule incidence and growth, as well as higher aminotransferase activity levels. After coffee + DEN co-treatment, the number of resulting HCC-like tumor lesions decreased in both mouse lines, but was still higher in mice carrying UGT1A SNPs. The reduced UGT1A activity and carcinogen detoxification may therefore represent a relevant risk factor for individual cancer disposition, which can, at least partially, be influenced by coffee consumption. The coffee-mediated activation of human UGT1A genes delivers a potential explanation for the decreased risk for HCC development and other liver diseases in coffee drinkers.
en
dc.language.isoeng
dc.rightsIn Copyright
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectUDP-Glukuronosyltransferasen
dc.subjectPolymorphismen
dc.subjectLeberfibrose
dc.subjectHepatozelluläres Karzinom
dc.subjectoxidativer Stress
dc.subjectCholestase
dc.subjectFettleber
dc.subjectUDP-glucuronosyltransferases
dc.subjectsingle nucleotide polymorphisms
dc.subjectliver fibrosis
dc.subjecthepatocellular carcinoma
dc.subjectoxidative stress
dc.subjectcholestasis
dc.subjectnon-alcoholic fatty liver disease
dc.subject.ddc500 Naturwissenschaften
dc.subject.ddc570 Biowissenschaften, Biologie
dc.titleImpact of UGT1A polymorphisms on inflammation and fibrogenesis in a humanized transgenic mouse model
dc.typeDissertation oder Habilitation
dc.publisher.nameUniversitäts- und Landesbibliothek Bonn
dc.publisher.locationBonn
dc.rights.accessRightsopenAccess
dc.identifier.urnhttps://nbn-resolving.org/urn:nbn:de:hbz:5-58913
ulbbn.pubtypeErstveröffentlichung
ulbbnediss.affiliation.nameRheinische Friedrich-Wilhelms-Universität Bonn
ulbbnediss.affiliation.locationBonn
ulbbnediss.thesis.levelDissertation
ulbbnediss.dissID5891
ulbbnediss.date.accepted18.06.2020
ulbbnediss.instituteMedizinische Fakultät / Kliniken : Medizinische Klinik und Poliklinik I - Allgemeine Innere Medizin
ulbbnediss.fakultaetMathematisch-Naturwissenschaftliche Fakultät
dc.contributor.coRefereeGruß, Oliver
ulbbnediss.date.embargoEndDate07.07.2021
ulbbnediss.contributor.gnd1239083637


Dateien zu dieser Ressource

Thumbnail

Das Dokument erscheint in:

Zur Kurzanzeige

Die folgenden Nutzungsbestimmungen sind mit dieser Ressource verbunden:

InCopyright