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A Fibroblast Growth Factor 21-Pregnane X Receptor Pathway Downregulates Hepatic CYP3A4 in Nonalcoholic Fatty Liver

Sarah J Woolsey1, Melanie D Beaton1, Sara E Mansell1

  • 1Department of Physiology and Pharmacology (S.J.W., J.Y., C.L.P., R.B.K., R.G.T), Division of Gastroenterology, Department of Medicine (M.D.B., P.C.A.), Division of Clinical Pharmacology, Department of Medicine (S.J.W., S.E.M., M.L.-P., J.Y., R.B.K., R.G.T.), Department of Paediatrics (C.L.P.), and Department of Oncology (C.L.P., R.B.K.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.

Molecular Pharmacology
|August 3, 2016
PubMed

Insights

Nonalcoholic fatty liver disease (NAFLD) elevates fibroblast growth factor 21 (FGF21), which reduces drug metabolism by decreasing CYP3A4 expression via the PXR pathway.

Area of Science:

  • Hepatology
  • Pharmacology
  • Endocrinology

Background:

  • Nonalcoholic fatty liver disease (NAFLD) is linked to altered drug metabolism.
  • Previous work showed NAFLD reduces CYP3A drug-metabolism activity and hepatic CYP3A4 expression.

Purpose of the Study:

  • Investigate the role of fibroblast growth factor 21 (FGF21) in regulating CYP3A4 expression in NAFLD.
  • Elucidate the molecular mechanisms underlying altered drug metabolism in NAFLD.

Main Methods:

  • Studied human subjects, mouse models, and cultured hepatoma cells (Huh7) with NAFLD.
  • Administered recombinant FGF21 and utilized FGF21 overexpression models.
  • Assessed CYP3A4 expression, activity, and nuclear localization of pregnane X receptor (PXR).
  • Inhibited FGF21 signaling using MEK1 kinase inhibitors.

Main Results:

  • Elevated FGF21 levels (circulating and hepatic) were observed in NAFLD models with reduced CYP3A4.
  • FGF21 administration or overexpression decreased CYP3A4 expression and activity.
  • Blocking FGF21 signaling restored CYP3A4 expression.
  • FGF21 treatment reduced nuclear PXR localization and its binding to the CYP3A4 promoter.

Conclusions:

  • An FGF21-PXR signaling pathway is implicated in reduced hepatic CYP3A4 metabolic activity in NAFLD.
  • FGF21 may contribute to altered drug response in patients with NAFLD.

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