NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY ADVANCE ONLINE PUBLICATION | 1 Department of Surgery, NUTRIM School of Nutrition, Toxicology and Metabolism, Maastricht University, PO Box 616, 6200 MD, Maastricht, Netherlands (F. G. Schaap). Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18–20, 1090 Vienna, Austria (M. Trauner). Department of Gastroenterology and Hepatology, Academic Medical Centre, Meibergdreef 9, 1105 AZ, Amsterdam, Netherlands (P. L. M. Jansen). Correspondence to: P. L. M. Jansen p.l.jansen@amc.uva.nl Bile acid receptors as targets for drug development Frank G. Schaap, Michael Trauner and Peter L. M. Jansen Abstract | The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades. These cascades affect the expression of a great number of target genes relevant for bile acid, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. Pregnane X receptor, vitamin D receptor and constitutive androstane receptor are additional nuclear receptors that respond to bile acids, albeit to a more restricted set of species of bile acids. Recognition of dedicated bile acid receptors prompted the development of semi-synthetic bile acid analogues and nonsteroidal compounds that target these receptors. These agents hold promise to become a new class of drugs for the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This Review discusses the relevant bile acid receptors, the new drugs that target bile acid signalling and their possible applications. Schaap, F. G. et al. Nat. Rev. Gastroenterol. Hepatol. advance online publication 27 August 2013; doi:10.1038/nrgastro.2013.151 Introduction Traditional Chinese medicine recognized the therapeutic value of bear bile long before the era of modern medicine. Bear bile is replete with ursodeoxycholic acid (UDCA), a bile acid encountered in appreciable amounts only in Ursidae. 1 Although bear bile gained scientific interest at the turn of the previous century with the isolation of a theretofore unknown bile acid (that is, UDCA) from bile of the polar bear by Olof Hammersten of the University of Uppsala in Sweden, 1 it would last nearly eight more decades before the therapeutic potential of bile acids for dissolv- ing gallstones and the treatment of bile acid biosynthesis defects and primary biliary cirrhosis (PBC) was realized. 2–4 An early observation was made in 1938 by Nobel laureate Philip Hench. He observed that rheumatic symptoms alleviated when patients with rheumatoid arthritis become jaundiced. 5 Elevation of serum bile acids has been a candi- date to explain this phenomenon ever since, and suggests an anti-inflammatory effect of bile acids. The discovery of receptors with affinity for bile acids, and subsequent X-ray crystallography studies of their ligand-binding sites, has given the development of natural, semi-synthetic and fully synthetic drugs targeting these receptors and associated pathways a strong impetus and molecular base. These new agents offer novel therapeutic possibilities for the treatment and prevention of liver disease, atherosclerosis, obesity and type 2 diabetes mellitus (T2DM). However, before this new approach can be fully appreciated, a more complete understanding is needed of the complex networks that link bile acids and metabolism. In reading this Review, one has to appreciate that much of the research in this area has been undertaken in mice, which often does not translate directly to humans. Working with human cell systems only partially remedies this situ- ation, as effects of bile acid signalling often rely on interac- tions between tissues rather than responses in single-cell systems. The final proof for the therapeutic value of bile acid analogues has to come from carefully planned, ran- domized human studies with clear end points. In this Review, we focus on bile acid signalling in humans, albeit it has to be acknowledged that much of the data and ideas are based on evidence from mouse models. Bile acids Excellent in-depth reviews covering the synthesis, metab- olism, transport and physicochemical functions of bile acids have been published elsewhere. 6–9 We will, therefore, only mention some elemental knowledge. Bile acids are a diverse class of water-soluble, cholesterol- derived, amphipathic molecules that are formed in the liver (primary bile acids) with microbial transformation in the gut (secondary bile acids) greatly expanding the molecu- lar repertoire. Bile acids typically occur as conjugates with either glycine or taurine, and are negatively charged over most of the physiological pH range. Although the term ‘bile salt’ would be more appropriate from a chemical perspec- tive, the expression ‘bile acid’ is mostly used throughout this Review for congruence with colloquial terminology (such as UDCA and obeticholic acid). These chemical fea- tures necessitate dedicated transport proteins for efficient cellular permeation and largely confine intracellular bile Competing interests M. Trauner declares associations with the following companies: Falk Pharma, Intercept, Phenex. See the article online for full details of the relationships. F. G. Schaap and P. L. M. Jansen declare no competing interests. REVIEWS © 2013 Macmillan Publishers Limited. All rights reserved