Bile Acid Receptors as Signal Integrators in Liver and Metabolism

Keystone Symposia, Silverthorne CO

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Abstract

ABSTRACT Support is requested for a Keystone Symposia meeting entitled Bile Acid Receptors as Signal Integrators in Liver and Metabolism, organized by Drs. Luciano Adorini, Kristina Schoonjans and Scott L. Friedman. The meeting will be held in Monterey, California from March 3-7, 2017. In the last decade, bile acids have enjoyed a renaissance, sparked by the identification at the turn of the millennium of their dedicated receptors, FXR and TGR5. This has been instrumental in revealing the key role bile acids play in regulating liver and metabolic homeostasis, transforming them from detergents facilitating the intestinal absorption of nutrients into versatile hormones. Signaling through FXR and TGR5 indeed modulates several metabolic pathways, regulating not only bile acid synthesis and enterohepatic recirculation, but also lipid, glucose and energy homeostasis. In addition, FXR and TGR5 agonists display anti-inflammatory and anti-fibrotic properties, making these agents interesting candidates for the treatment of several liver and metabolic diseases, including nonalcoholic steatohepatitis (NASH). NASH is already a medical problem of epidemic proportions poised to become by 2020 the leading indication for liver transplantation in the US. This conference will review genetics, structure and functions of bile acid receptors and will explore the intricate interactions among gut microbiota, bile acids and liver disease, as well as the multiple bidirectional signals along the gut-liver axis. Intriguingly, FXR agonists, like the bile acid derivative obeticholic acid, could have a beneficial role in the treatment of NASH by decreasing hepatic lipogenesis, steatosis and insulin resistance, while also inhibiting inflammatory and fibrogenic responses able to promote liver cirrhosis and hepatocellular carcinoma. The conference therefore aims at integrating basic, translational and clinical aspects of bile acid receptors, bringing together an interdisciplinary group of scientists to discuss the state of the art and propose new avenues of investigation in this active and dynamic field. Relevance to NIDDK: NIDDK conducts and supports medical research and research training to disseminate science-based information in key areas related to its mission, including endocrine and metabolic diseases, digestive diseases, and obesity. NIDDK has recently sponsored the phase 2 study of obeticholic acid in NASH patients (FLINT trial), and this conference will integrate the study results into a broader perspective of disease pathogenesis and therapeutic intervention in metabolic liver disease, which is the fastest rising liver disease in the United States.