Reversal of metabolic disorders by pharmacological activation of bile acid receptors TGR5 and FXR

Mol Metab. 2018 Mar:9:131-140. doi: 10.1016/j.molmet.2018.01.005. Epub 2018 Jan 11.


Objectives: Activation of the bile acid (BA) receptors farnesoid X receptor (FXR) or G protein-coupled bile acid receptor (GPBAR1; TGR5) improves metabolic homeostasis. In this study, we aim to determine the impact of pharmacological activation of bile acid receptors by INT-767 on reversal of diet-induced metabolic disorders, and the relative contribution of FXR vs. TGR5 to INT-767's effects on metabolic parameters.

Methods: Wild-type (WT), Tgr5-/-, Fxr-/-, Apoe-/- and Shp-/- mice were used to investigate whether and how BA receptor activation by INT-767, a semisynthetic agonist for both FXR and TGR5, could reverse diet-induced metabolic disorders.

Results: INT-767 reversed HFD-induced obesity dependent on activation of both TGR5 and FXR and also reversed the development of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Mechanistically, INT-767 improved hypercholesterolemia by activation of FXR and induced thermogenic genes via activation of TGR5 and/or FXR. Furthermore, INT-767 inhibited several lipogenic genes and de novo lipogenesis in the liver via activation of FXR. We identified peroxisome proliferation-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα) as novel FXR-regulated genes. FXR inhibited PPARγ expression by inducing small heterodimer partner (SHP) whereas the inhibition of CEBPα by FXR was SHP-independent.

Conclusions: BA receptor activation can reverse obesity, NAFLD, and atherosclerosis by specific activation of FXR or TGR5. Our data suggest that, compared to activation of FXR or TGR5 only, dual activation of both FXR and TGR5 is a more attractive strategy for treatment of common metabolic disorders.

Keywords: Atherosclerosis; Farnesoid X receptor; NAFLD; Obesity; TGR5.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bile Acids and Salts / pharmacology
  • Bile Acids and Salts / therapeutic use*
  • Diet, High-Fat / adverse effects
  • Hep G2 Cells
  • Humans
  • Hypercholesterolemia / drug therapy*
  • Hypercholesterolemia / etiology
  • Hypercholesterolemia / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / drug therapy*
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Obesity / drug therapy*
  • Obesity / etiology
  • Obesity / metabolism
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, G-Protein-Coupled / agonists*


  • 6-ethyl-24-norcholane-3,7,23-triol-23 sulfate
  • Bile Acids and Salts
  • Gpbar1 protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, G-Protein-Coupled
  • farnesoid X-activated receptor