Understanding the molecular mechanisms of bile acid receptor activation for the treatment of human liver disease
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 gallstone formation in susceptible patients. In this randomized, double-blinded placebo control trial Obeticholic Acid in Gallstone Surgery (OCAGS), 20 patients were randomised to either OCA 25 mg/day or a matching placebo for 3 weeks prior to undergoing a laparoscopic cholecystectomy. Bile acids, fibroblast growth factor 19 (FGF19) and lipids were measured both in serum and gallbladder bile before and after treatment. The index of cholesterol saturation and bile acid pool hydrophobicity were calculated and both were higher in the OCA treated group, implying a higher risk of cholelithiasis. Gene analysis suggested a biliary origin of FGF19. We concluded that treatment with OCA leads to a higher risk of gallstone formation. Paper III investigates how bile acids and FXR interactions modulate metabolic phenotypes in humans. In this double-blinded randomized control trial Obeticholic Acid in Bariatric Surgery & Gallstone Surgery OCABSGS, we explored the effects of FXR activation on bile acid turnover. We found by performing ChIP-Seq that the expression of FXR-DNA binding sites was not related to OCA-treatment; rather, it seems to be predetermined by the phenotype (obese vs non-obese). In contrast, RNA-Seq indicated induction of FXR target genes by OCA as compared to placebo. In conclusion, our experiments explore a novel treatment modality for pruritus patients with cholestatic liver disease. However, given the side effects, the clinical applicability of this compound is doubtful. Our studies also offer a unique insight into gallbladder pathophysiology and the mechanisms leading to the formation of gallstones in susceptible populations during treatment with FXR agonists. We have also shown that FXR transcriptional signalling in human DNA is altered in the obese phenotype, which may underlie aberrant metabolism and liver function in obesity.
Parts of work
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/s41598-018-25214-0II. 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.2019.06.011III. 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.
Doctor of Philosophy (Medicine)
University of Gothenburg. Sahlgrenska Academy
Institute of Medicine. Department of Molecular and Clinical Medicine
Torsdagen den 11 juni 2020, kl 9.00, Hörsal Arvid Carlsson, Academicum, Medicinaregatan 3, Göteborg https://gu-se.zoom.us/j/63713442426?pwd=dVJ3R2xkQ000aDcvUnpyMmh4bVV1QT09
Date of defence
Gastroenterologi och hepatologi