التفاصيل البيبلوغرافية
| العنوان: |
Understanding the molecular mechanisms of bile acid receptor activation for the treatment of human liver disease |
| المؤلفون: |
Al-Dury, Samer |
| سنة النشر: |
2020 |
| المجموعة: |
University of Gothenburg: GUPEA (Gothenburg University Publications Electronic Archive) |
| مصطلحات موضوعية: |
Medicinska sjukdomar, Gastroenterologi och hepatologi, FXR, IBAT, Gallsyror, Obesitas, Gallstenar |
| الوصف: |
Farnesoid X receptor (FXR) is a nuclear transcription factor that is activated by bile acids and regulates bile acid homeostasis, glucose and lipid metabolism. FXR activation by a ligand has been identified as a therapeutic modality for a range of liver and metabolic diseases. Although bile acids and FXR are known to be key players in the interplay between the liver, gastrointestinal tract, lipid and glucose metabolism, the interactions are complex and not well understood. To date, FXR activation studies to decipher the underlying molecular mechanisms of its action have almost exclusively been conducted in mouse models, which are of limited human relevance due to interspecies differences between mice and humans in bile acid composition, metabolism and FXR activation patterns. Looking at bile acid homeostasis from another angle; the apical sodium-dependent bile acid transporter (ASBT; also known as ileal bile acid transporter (IBAT)) is an important FXR target gene and it is pivotal for the physiological reabsorption of conjugated bile acids from the ileum back to the liver. IBAT inhibition results in an increased bile acid load in the colon and subsequently a lower bile acid pool. To date, IBAT inhibitors have been used in animal models for the treatment of non-alcoholic steatohepatitis (NASH), and in humans they have been sparsely tested in clinical trials for the treatment of chronic constipation and severe itch that is associated with cholestatic liver diseases, such as primary biliary cholangitis (PBC) and pediatric liver disease. Paper I presents a prospective open-label phase IIa pilot study with IBAT inhibitor A4250 to assess the safety and efficacy of this compound in alleviating itch in patients with PBC. In this study, 10 patients with PBC were treated with A4250 for four weeks. Despite some subjective improvements in pruritus severity, the study needed to be stopped prematurely because of abdominal side effects. Paper II examines how the FXR agonist obeticholic acid (OCA) may increase the risk of ... |
| نوع الوثيقة: |
doctoral or postdoctoral thesis |
| وصف الملف: |
application/pdf |
| اللغة: |
English |
| العلاقة: |
I. Al-Dury S, Wahlström A, Wahlin S, Langedijk J, Elferink R O, Ståhlman M, & Marschall HU (2018). Pilot study with IBAT inhibitor A4250 for the treatment of cholestatic pruritus in primary biliary cholangitis. Scientific Reports 2018; 8(1):6658. ::doi::10.1038/s41598-018-25214-0; II. Al-Dury S, Wahlström A, Panzitt K, Thorell A, Ståhlman M, Trauner M, Fickert P, Bäckhed F, Fändriks L, Wagner M & Marschall HU. Obeticholic acid may increase the risk of gallstone formation in susceptible patients. Journal of Hepatology 2019; 71(5): 986–991. ::doi::10.1016/j.jhep.2019.06.011; III. Jungwirth E, Panzitt K, Al-Dury S, Wahlström A, Thorell A, Ståhlman M, Fickert P, Fändriks L, Wagner M & Marschall HU. Human FXR-DNA binding is associated to the obese phenotype. Manuscript.; http://hdl.handle.net/2077/63239Test |
| الإتاحة: |
http://hdl.handle.net/2077/63239Test |
| رقم الانضمام: |
edsbas.41DAFB47 |
| قاعدة البيانات: |
BASE |
