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Simultaneous inhibition of FXR and TGR5 exacerbates atherosclerotic formation

Shinobu Miyazaki-Anzai1, Masashi Masuda1, Shohei Kohno1

  • 1Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, CO 80045.

Journal of Lipid Research
|July 7, 2018
PubMed

Insights

Simultaneously activating farnesoid X receptor (FXR) and TGR5 reduces atherosclerosis. Blocking both receptors worsens disease, indicating dual activation is key for INT-767

Area of Science:

  • Cardiovascular Research
  • Metabolic Diseases
  • Pharmacology

Background:

  • Atherosclerosis involves lipid accumulation and inflammation in arteries.
  • Bile acid receptors, farnesoid X receptor (FXR) and TGR5, are implicated in metabolic regulation.
  • Simultaneous activation of FXR and TGR5 by INT-767 shows promise in reducing atherosclerosis.

Purpose of the Study:

  • To investigate the impact of simultaneously inactivating FXR and TGR5 on atherosclerosis.
  • To determine which bile acid receptor mediates the anti-atherogenic effects of INT-767.

Main Methods:

  • Generated LDL receptor knockout (LDLR KO) mice with dual FXR and TGR5 deficiency.
  • Administered INT-767 to assess its effects on atherosclerosis, lipid levels, and aortic inflammation.
  • Analyzed nuclear factor κB activation and cytokine/chemokine levels.

Main Results:

  • Dual deficiency of FXR and TGR5 exacerbated atherosclerosis and aortic inflammation.
  • INT-767's lipid-lowering effect was blocked by FXR deficiency alone.
  • INT-767's anti-atherogenic and anti-inflammatory effects were abolished by dual FXR and TGR5 deficiency.

Conclusions:

  • Dual activation of FXR and TGR5 is crucial for INT-767's anti-atherogenic and anti-inflammatory actions.
  • The anti-atherogenic effect of INT-767 relies on its anti-inflammatory, not lipid-lowering, properties via dual receptor activation.
  • Simultaneous FXR and TGR5 activation represents a promising therapeutic strategy for atherosclerosis.
Keywords:
atherosclerosisbile acidinflammation

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