Review
Bile-acid-activated receptors: targeting TGR5 and farnesoid-X-receptor in lipid and glucose disorders

https://doi.org/10.1016/j.tips.2009.08.001Get rights and content

Bile acids are a family of steroid molecules generated in the liver by cholesterol oxidation. In addition to their role in nutrient absorption, bile acids are signaling molecules that exert genomic and non-genomic effects by activating TGR5 (M-BAR, GP-BAR1 or BG37) a G-protein-coupled receptor, and farnesoid X receptor (FXR), a member of the nuclear hormone receptor superfamily. Ligands for these receptors might be beneficial in treating disorders of lipid and glucose homeostasis. TGR5 ligands decrease blood glucose levels and increase energy expenditure by promoting intracellular thyroid hormone activation in thermogenically competent tissues. FXR agonists repress the synthesis of endogenous bile acids and reduce triglyceride, cholesterol and glucose plasma levels and are currently being tested in nonalcoholic steatohepatitis. FXR modulators are being developed to target selective gene clusters and avoid the negative impact of FXR on HDL biosynthesis. The development of dual FXR and TGR5 ligands could provide new opportunities for the treatment of lipid and glucose disorders.

Introduction

In 1988, Reaven described the metabolic syndrome as a link between insulin resistance and hypertension, dyslipidemia, type 2 diabetes and other metabolic abnormalities associated with an increased risk of atherosclerotic cardiovascular disease [1]. The prevalence of metabolic disorders linked to insulin resistance and diabetes is increasing at an alarming rate. The increasing prevalence of overweight and obesity is leading to an upsurge in cases of diabetes and hypertension. Obesity and diabetes represent a global healthcare problem that is threatening to reach pandemic levels [2]. First-line therapy for the metabolic syndrome is a lifestyle change involving weight reduction and increased physical activity. Unfortunately, lifestyle therapy can be difficult to implement in practice and treatment of these disorders requires the use of multiple drugs. Despite exponential growth in the number of clinically effective treatments, multi-therapies expose the patients to side effects and there is increased interest in the development of safer therapies that could positively affect multiple targets.

Section snippets

Bile acids and their receptors

Bile acids, the main active constituents of bile, are amphipathic molecules placed at the interface between nutrient absorption and metabolism [3]. Their amphipathic nature is essential for the solubilization of dietary lipids and promotion of their absorption in the digestive tract. The principal bile acids in humans are the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA), as well as their glycine and taurine conjugates, and the secondary bile acids deoxycholic acid (DCA)

Bile-acid-activated GPCRs: TGR5

TGR5, a member of the rhodopsin-like superfamily of GPCRs that transduces signals through Gs protein (α–βγ subunits), was identified as an LCA-activated receptor by two different groups in 2002 and 2003 4, 6. TGR5 activation leads to cAMP accumulation and receptor internalization. Primary and secondary bile acids activate the receptor at nanomolar concentrations (Table 1). LCA and taurolithocholic acid (TLCA) activate the receptor with an EC50 of ∼600 and 300 nM, respectively, and should be

Nuclear hormone receptors: FXR

FXR is a member of the nuclear receptor superfamily and is highly expressed in liver, intestine, kidney and adrenal glands 5, 20, 21, 22, 23, 24, 25. CDCA activates the receptor at an EC50 of ∼10 μM and is a physiological ligand of FXR (Table 1). FXR is activated by TGR5 ligands LCA, DCA and CA, but at higher concentrations than that observed for CDCA 5, 25, 26, 27. The FXR gene is conserved from humans to fish [5]. The single FXRA gene in humans and primates encodes four FXRα isoforms

Strategies for targeting bile acid receptors

TGR5 and FXR are emerging as important targets for treating disorders of lipid and glucose homeostasis.

Conclusions

Pharmacological and molecular approaches have shown that bile-acid-activated signals are promising targets in the treatment of dyslipidemia, cholesterol-related disorders, obesity and type 2 diabetes. Steroidal FXR ligands are currently being tested against NASH. Preclinical studies have shown that FXR agonists carry some intrinsic toxicity linked to CYP7A1-mediated repression of the synthesis of endogenous bile acids and to inhibition of APO-AI synthesis that could lead to a reduction in

References (87)

  • M. Downes

    A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR

    Mol. Cell

    (2003)
  • S. Fiorucci

    Targeting FXR for liver and metabolic indications

    Trends Mol. Med.

    (2007)
  • S.A. Van Mil

    Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy

    Gastroenterology

    (2007)
  • F.L. Lee

    FXR, a multipurpose nuclear receptor

    Trends Biochem. Sci.

    (2006)
  • B. Goodwin

    A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis

    Mol. Cell

    (2000)
  • T.T. Lu

    Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors

    Mol. Cell

    (2000)
  • C. Stedman

    Feed-forward regulation of bile acid detoxification by CYP3A4: studies in humanized transgenic mice

    J. Biol. Chem.

    (2004)
  • T.A. Kerr

    Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis

    Dev. Cell

    (2002)
  • L.A. Denson

    The orphan nuclear receptor, Shp, mediates bile acid-induced inhibition of the rat bile acid transporter

    Gastroenterology

    (2001)
  • C. Yu

    Independent repression of bile acid synthesis and activation of c-Jun N-terminal kinase (JNK) by activated hepatocyte fibroblast growth factor receptor 4 (FGFR4) and bile acids

    J. Biol. Chem.

    (2005)
  • T. Inagaki

    Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis

    Cell Metab.

    (2005)
  • D.J. Shin et al.

    FGF15/FGFR4 integrates growth factor signaling with hepatic bile acid metabolism and insulin action

    J. Biol. Chem.

    (2009)
  • D. Jung

    FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption

    J. Lipid Res.

    (2007)
  • I. Kim

    Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine

    J. Lipid Res.

    (2007)
  • G. Lambert

    The farnesoid X-receptor is an essential regulator of cholesterol homeostasis

    J. Biol. Chem.

    (2003)
  • E.A. Hanniman

    Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice

    J. Lipid Res.

    (2005)
  • H.B. Hartman

    Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR–/– and apoE–/– mice

    J Lipid Res.

    (2009)
  • K. Yamagata

    Bile acids regulate gluconeogenic gene expression via small heterodimer partner-mediated repression of hepatocyte nuclear factor 4 and Foxo1

    J. Biol. Chem.

    (2004)
  • D. Duran-Sandoval

    The farnesoid X receptor modulates hepatic carbohydrate metabolism during the fasting–refeeding transition

    J. Biol. Chem.

    (2005)
  • B. Cariou

    The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice

    J. Biol. Chem.

    (2006)
  • L.Z. Mi

    Structural basis for bile acid binding and activation of the nuclear receptor FXR

    Mol. Cell

    (2003)
  • T. Zhang

    3D-QSAR studies with the aid of molecular docking for a series of non-steroidal FXR agonists

    Bioorg. Med. Chem. Lett.

    (2007)
  • T. Suzuki

    The novel compounds that activate farnesoid X receptor: the diversity of their effects on gene expression

    J. Pharmacol. Sci.

    (2008)
  • K.A. Houck

    T0901317 is a dual LXR/FXR agonist

    Mol. Genet. Metab.

    (2004)
  • I. Dussault

    Identification of gene-selective modulators of the bile acid receptor FXR

    J. Biol. Chem.

    (2003)
  • J. Cui

    Guggulsterone is a farnesoid X receptor antagonist in coactivator association assays but acts to enhance transcription of bile salt export pump

    J. Biol. Chem.

    (2003)
  • G.M. Reaven

    Role of insulin resistance in human disease

    Diabetes

    (1988)
  • D.W. Russell

    The enzymes, regulation, and genetics of bile acid synthesis

    Annu. Rev. Biochem.

    (2003)
  • D.D. Moore

    International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor α, farnesoid X receptor β, liver X receptor α, liver X receptor β, and vitamin D receptor

    Pharmacol. Rev.

    (2006)
  • H. Sato

    Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure, activity relationships, and molecular modeling studies

    J. Med. Chem.

    (2008)
  • R. Pellicciari

    Nongenomic actions of bile acids. Synthesis and preliminary characterization of 23- and 6,23-alkyl-substituted bile acid derivatives as selective modulators for the G-protein coupled receptor TGR5

    J. Med. Chem.

    (2007)
  • C. Thomas

    Targeting bile-acid signalling for metabolic diseases

    Nat. Rev. Drug Discov.

    (2008)
  • M. Watanabe

    Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation

    Nature

    (2006)
  • Cited by (268)

    View all citing articles on Scopus
    View full text