Avhandlingar och publikationer
Understanding the molecular mechanisms of bile acid receptor activation for the treatment of human liver disease
Publicerad 9 september 2020
Understanding the molecular mechanisms of bile acid receptor activation for the treatment of human liver disease Samer Al-Dury, Department of Clinical and Molecular Medicine Institute of Medicine Sahlgrenska Academy, University of Gothenburg, 2020
Bile acids (BAs) are unique amphipathic molecules with multiple functions (1). They are synthesized from cholesterol in the liver and are the major lipid component of bile. One of their major functions is the regulation of cholesterol metabolism. After a meal ingestion, BAs are pumped by the gallbladder and this way enter the gastrointestinal tract. BAs function as key regulators of fat emulsification and solubilization, the two rate limiting steps in the process of fat digestion and absorption of cholesterol, triglycerides (TG) and the associated fat-soluble vitamins A, D, E & K (1). BAs also act as signaling molecules by activating the two main BA sensors in the body: the nuclear receptor Farnesoid X receptor (FXR), and the cell surface receptor Takeda G-protein receptor 5 (TGR5), and different BAs act as agonists and antagonists of those receptors in a varying degree (2, 3). In recent years, BAs have been identified as key regulators of complex pathways at a systemic level ranging from their own homeostasis to cholesterol, TG, glucose and
energy metabolism. Additional regulations include cell proliferation, inflammation, and tumor onset and progression (1). The heterogenicity of BA functions is therefore key to their involvement in an array of metabolic and liver diseases, such as obesity, type 2 diabetes mellitus, chronic liver and biliary diseases (4). The studies presented in this thesis aim to shed a light on the molecular mechanisms involved in BA regulation, closely looking at BA – FXR interactions and their downstream effect on various disease conditions, as well as answer some of the questions regarding the precise impact of BAs on lipid metabolism. Finally, we studied how pharmacological interruption of the enterohepatic circulation (EHC) may reduce the circulating BA pool in cholestatic patients and thus alleviate pruritus that is commonly associated with cholestatic conditions.
Uppdaterad: 9 november 2022
