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.

Fibroblast growth factor 19 (FGF19) is an endocrine factor produced by the small intestine in response to uptake of luminal bile salts. In the liver, FGF19 binds to FGF receptor-4, resulting in down-regulation of cytochrome P (CYP) 7A1 and reduced bile salt synthesis. Down-regulation of CYP7A1 under cholestatic conditions has been attributed to bile salt-mediated induction of the transcriptional repressor short heterodimer partner (SHP), because the interrupted enterohepatic cycle of bile salts is thought to abrogate intestinal FGF19 production and thus result in lowering of plasma FGF19 levels. Unexpectedly, we observed marked elevation of plasma FGF19 in patients with extrahepatic cholestasis caused by a pancreatic tumor (2.3 ؎ 2.3 in cholestatic versus 0.40 ؎ 0.25 ng/mL and 0.29 ؎ 0.12 ng/mL in postcholestatic patients who received preoperative drainage by biliary stenting, P ‫؍‬ 0.004, and noncholestatic control patients, P ‫؍‬ 0.04, respectively). Although FGF19 messenger RNA (mRNA) is virtually absent in normal liver, FGF19 mRNA was strongly increased (31-fold to 374-fold, P < 0.001) in the liver of cholestatic patients in comparison with drained and control patients. In the absence of changes in SHP mRNA, CYP7A1 mRNA was strongly reduced (7.2-fold to 24-fold, P < 0. B ecause they are potent detergents, synthesis of bile salts is subject to rigorous regulation. 1,2 The principal target for control of bile salt synthesis is the cytochrome P (CYP) 7A1 gene, which encodes the ratedetermining enzyme in the dominant biosynthetic pathway. Regulation of CYP7A1 occurs primarily at the transcriptional level and involves several nuclear hormone receptors. Among these ligand-activated transcription factors, the bile salt receptor FXR (farnesoid-X receptor) plays a key role in bile salt-mediated repression of CYP7A1. 2-4 Activation of hepatic FXR induces expression of short heterodimer partner (SHP), a transcriptional repressor that diminishes the transactivation potential of several transcription factors required for efficient CYP7A1 expression. [3][4][5] Activation of intestinal FXR by reabsorbed bile salts induces expression and portal release of FGF19 (fibroblast growth factor 19, termed Fgf15 in rodents). 6,7 Binding of FGF19/ Fgf15 to the cell surface receptor FGFR4 results in activation of mitogen-activated protein kinase pathways and downregulation of CYP7A1. 7,8 Studies in mice with intestine-specific or liver-specific disruption of the Fxr gene revealed that administration of a synthetic FXR agonist failed to repress Cyp7a1 in animals deficient in intestinal Fxr. 9 This study thus implied an important role for intestinal Fgf15 in regulation of bile salt synthesis.

ApoAV has been discovered recently as a novel modifier of triglyceride (TG) metabolism, but the pathways involved are currently unknown. To gain insight into the function of apoAV, adenovirus-mediated gene transfer of murine apoa5 to C57Bl/6 mice was employed. The injection of low doses of Ad-apoa5 (1-5 ؋ 10 8 plaqueforming units/mouse) dose-dependently reduced plasma very low density lipoprotein (VLDL)-TG levels. First, we evaluated whether a reduced hepatic VLDL production contributed to the TG-lowering effect. Ad-apoa5 treatment dose-dependently diminished (29 -37%) the VLDL-TG production rate without affecting VLDL particle production, suggesting that apoAV impairs the lipidation of apoB. Second, Ad-apoa5 treatment dose-dependently reduced (68 -88%) the postprandial hypertriglyceridemia following an intragastric fat load, suggesting that apoAV also stimulates the lipoprotein lipase (LPL)-dependent clearance of TG-rich lipoproteins. Indeed, recombinant apoAV was found to dose-dependently stimulate LPL activity up to 2.3-fold in vitro. Accordingly, intravenously injected VLDL-like TG-rich emulsions were cleared at an accelerated rate concomitant with the increased uptake of emulsion TG-derived fatty acids by skeletal muscle and white adipose tissue in Ad-apoa5-treated mice. From these data, we conclude that apoAV is a potent stimulator of LPL activity. Thus, apoAV lowers plasma TG by both reducing the hepatic VLDL-TG production rate and by enhancing the lipolytic conversion of TG-rich lipoproteins.Hypertriglyceridemia is a risk factor for coronary heart disease independent from the well known risk factors such as elevated LDL 1 and reduced HDL cholesterol levels (1). Recently, a novel apolipoprotein, apoAV, has been identified that strongly influences plasma triglyceride (TG) levels (2, 3). The human APOA5 gene is part of the apolipoprotein gene cluster on chromosome 11q23 that also encompasses APOA1, APOC3, and APOA4. An initial study revealed the association of three single nucleotide polymorphisms within the APOA5 locus with plasma TG levels and VLDL mass in humans (2). Importantly, these metabolic effects were not associated with a genetic marker in the nearby APOC3 gene that is also known to affect plasma TG levels (2). Subsequent studies in diverse ethnic groups uncovered additional single nucleotide polymorphisms including apoAV protein variants and further supported a role for common genetic variations in APOA5 in influencing plasma TG levels (4, 5). Interestingly, in a recent study, minor allele frequencies of 3 of 5 studied single nucleotide polymorphisms were found to be significantly higher in a hypertriglyceridemic population (4).Mouse models confirmed the TG-modulating effects of apoAV observed in humans. Mice expressing a human APOA5 transgene showed a 65% decrease in plasma TG levels compared with control mice (2). Conversely, apoa5 knock-out mice showed a 400% increase in plasma TG concentration (2). Interestingly, the adenovirus-mediated expression of apoAV in mice resulted in a decrease of b...

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