Dual activation of the bile acid nuclear receptor FXR and G-protein-coupled receptor TGR5 protects mice against atherosclerosis

PLoS One. 2014 Sep 19;9(9):e108270. doi: 10.1371/journal.pone.0108270. eCollection 2014.


Bile acid signaling is a critical regulator of glucose and energy metabolism, mainly through the nuclear receptor FXR and the G protein-coupled receptor TGR. The purpose of the present study was to investigate whether dual activation of FXR and TGR5 plays a significant role in the prevention of atherosclerosis progression. To evaluate the effects of bile acid signaling in atherogenesis, ApoE-/- mice and LDLR-/- mice were treated with an FXR/TGR5 dual agonist (INT-767). INT-767 treatment drastically reduced serum cholesterol levels. INT-767 treatment significantly reduced atherosclerotic plaque formation in both ApoE-/- and LDLR-/- mice. INT-767 decreased the expression of pro-inflammatory cytokines and chemokines in the aortas of ApoE-/- mice through the inactivation of NF-κB. In addition, J774 macrophages treated with INT-767 had significantly lower levels of active NF-κB, resulting in cytokine production in response to LPS through a PKA dependent mechanism. This study demonstrates that concurrent activation of FXR and TGR5 attenuates atherosclerosis by reducing both circulating lipids and inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / genetics*
  • Atherosclerosis / metabolism
  • Bile Acids and Salts / metabolism*
  • Bile Acids and Salts / pharmacology
  • Bile Acids and Salts / physiology
  • Cell Line
  • Cholesterol / blood
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, G-Protein-Coupled / physiology*
  • Signal Transduction / drug effects
  • Triglycerides / blood


  • 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
  • Triglycerides
  • farnesoid X-activated receptor
  • Cholesterol