Trends in Pharmacological Sciences
ReviewBile-acid-activated receptors: targeting TGR5 and farnesoid-X-receptor in 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
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