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Targeting bile-acid signalling for metabolic diseases

Key Points

  • Hepatic synthesis of bile acids is the primary pathway for cholesterol catabolism. The cholesterol 7α-hydroxylase enzyme (encoded by CYP7A1) represents the rate-limiting step of the multi-enzymatic bile-acid biosynthetic pathway.

  • Bile acids play a crucial role in dietary lipid digestion and absorption, and also act as versatile signalling molecules through the activation of the nuclear hormone receptor farnesoid X receptor-α (FXR-α) and the recently identified G-protein-coupled receptor TGR5.

  • Bile-acid-mediated activation of FXR-α-signalling pathways regulate the enterohepatic recycling of bile acids, protect against their accumulation in the liver and inhibit their own biosynthesis.

  • Through their endocrine function, bile acids also activate TGR5 signalling pathways in multiple cells, through which they control immune function, liver and gall-bladder physiology and glucose and energy homeostasis.

  • The development of TGR5 agonists could have benefits to combat many aspects of the metabolic syndrome, whereas FXR-α agonists could hold promise for reducing hypertriglyceridaemia and modulating glucose metabolism. Pharmaceutical activation of these bile-acid-signalling pathways is therefore a novel way to improve metabolism.


Bile acids are increasingly being appreciated as complex metabolic integrators and signalling factors and not just as lipid solubilizers and simple regulators of bile-acid homeostasis. It is therefore not surprising that a number of bile-acid-activated signalling pathways have become attractive therapeutic targets for metabolic disorders. Here, we review how the signalling functions of bile acids can be exploited in the development of drugs for obesity, type 2 diabetes, hypertriglyceridaemia and atherosclerosis, as well as other associated chronic diseases such as non-alcoholic steatohepatitis.

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Figure 1: Bile-acid synthesis pathways.
Figure 2: Structure and hydrophobic/hydrophilic profile of bile acids.
Figure 3: Overview of the bile-acid transport system.
Figure 4: FXR-mediated genomic actions of bile acids.
Figure 5: TGR5: a dedicated membrane bile-acid receptor.
Figure 6: A model for the TGR5 ligand binding pocket.


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The authors acknowledge support by grants from the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Université Louis Pasteur, the Hôpital Universitaire de Strasbourg, the National Institutes of Health (DK59820 and DK067320), L'Agence Nationale pour la Recherche (ANR 07-PHYSIO-003-01), La Fondation pour la Recherche Médicale, Ligue contre le Cancer, Intercept Pharmaceuticals (New York, USA), the Ecole Polytechnique Federale de Lausanne and the European Union (LSHM-CT-2004-512,013), and by fellowships from Société Française de Nutrition and L'Association pour la Recherche sur le Cancer (to C.T.). We apologize to those authors whose original work could not be quoted owing to space restrictions.

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Correspondence to Johan Auwerx or Kristina Schoonjans.

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J.A. and R.P. are consultants for Intercept Pharmaceuticals, and M.P. is CEO of Intercept Pharmaceuticals, a company that is developing FXR-α and TGR5 ligands.

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Thomas, C., Pellicciari, R., Pruzanski, M. et al. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov 7, 678–693 (2008).

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