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Subcutaneous Administration of Muscarinic Antagonists and Triple-Immunostaining of the Levator Auris Longus Muscle in Mice
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Farnesoid X receptor antagonist exacerbates dyslipidemia in mice

Yuichiro Amano1, Hiroko Yamakawa1, Kazuko Yonemori1

  • 1Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.

Pharmacological Reports : PR
|January 26, 2018
PubMed
Abstract

Insights

The farnesoid X receptor (FXR) antagonist, compound-T0, worsened lipid profiles in mice. This occurred because it increased intestinal lipid absorption by accelerating bile acid excretion, highlighting a novel mechanism in dyslipidemia.

Area of Science:

  • Pharmacology
  • Biochemistry
  • Metabolic Diseases

Background:

  • Farnesoid X receptor (FXR) antagonists' effects on plasma lipid profiles remain largely unstudied.
  • Dyslipidemia is a significant risk factor for cardiovascular disease, necessitating novel therapeutic targets.

Purpose of the Study:

  • To investigate the antidyslipidemic effects of an FXR antagonist, compound-T0, in dyslipidemic mouse models.
  • To elucidate the underlying mechanisms responsible for compound-T0's lipid-modulating effects.

Main Methods:

  • Oral administration of compound-T0 (1-100 mg/kg) to C57BL/6J and low-density lipoprotein receptor knockout (LDLR-/-) mice on a Western-type diet.
  • Assessment of plasma lipid levels, very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) clearance, hepatic triglyceride secretion, and intestinal cholesterol absorption.

Main Results:

  • Compound-T0 significantly elevated non-high-density lipoprotein cholesterol in both mouse strains and triglyceride levels in LDLR-/- mice.
  • The FXR antagonist did not improve LDL clearance or affect triglyceride clearance and hepatic secretion.
  • Compound-T0 significantly enhanced intestinal cholesterol absorption in LDLR-/- mice.

Conclusions:

  • The FXR antagonist, compound-T0, exacerbated dyslipidemia in mice.
  • This exacerbation was attributed to enhanced intestinal lipid absorption mediated by accelerated bile acid excretion.
Keywords:
Compound-T0DyslipidemiaFarnesoid X receptor antagonistLDL receptor knockout mouseSpecies difference

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