title: A Fibroblast Growth Factor 21-Pregnane X Receptor Pathway Downregulates Hepatic CYP3A4 in Nonalcoholic Fatty Liver Disease.
abstract: Nonalcoholic fatty liver disease (NAFLD) alters drug response. We previously reported that NAFLD is associated with reduced in vivo CYP3A drug-metabolism activity and hepatic CYP3A4 expression in humans as well as mouse and human hepatoma models of the disease. Here, we investigated the role of the lipid- and glucose-modulating hormone fibroblast growth factor 21 (FGF21) in the molecular mechanism regulating CYP3A4 expression in NAFLD. In human subjects, mouse and cellular NAFLD models with lower CYP3A4 expression, circulating FGF21, or hepatic FGF21 mRNA levels were elevated. Administration of recombinant FGF21 or transient hepatic overexpression of FGF21 resulted in reduced liver CYP3A4 luciferase reporter activity in mice and decreased CYP3A4 mRNA expression and activity in cultured Huh7 hepatoma cells. Blocking canonical FGF21 signaling by pharmacological inhibition of MEK1 kinase in Huh7 cells caused de-repression of CYP3A4 mRNA expression with FGF21 treatment. Mice with high-fat diet-induced simple hepatic steatosis and lipid-loaded Huh7 cells had reduced nuclear localization of the pregnane X receptor (PXR), a key transcriptional regulator of CYP3A4 Furthermore, decreased nuclear PXR was observed in mouse liver and Huh7 cells after FGF21 treatment or FGF21 overexpression. Decreased PXR binding to the CYP3A4 proximal promoter was found in FGF21-treated Huh7 cells. An FGF21-PXR signaling pathway may be involved in decreased hepatic CYP3A4 metabolic activity in NAFLD.
authors.affiliation: Department 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.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Woolsey
authors.affiliation: Department 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.
authors.forename: Melanie D
authors.initials: MD
authors.lastname: Beaton
authors.affiliation: Department 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.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Mansell
authors.affiliation: Department 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.
authors.forename: Matilde
authors.initials: M
authors.lastname: Leon-Ponte
authors.affiliation: Department 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.
authors.forename: Janice
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department 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.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Pin
authors.affiliation: Department 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.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Adams
authors.affiliation: Department 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.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
authors.affiliation: Department 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 rommel.tirona@schulich.uwo.ca.
authors.forename: Rommel G
authors.initials: RG
authors.lastname: Tirona
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D000090265:Klotho Proteins; D008099:Liver; D020935:MAP Kinase Signaling System; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism*; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000077297:Pregnane X Receptor; D017468:Receptors, Fibroblast Growth Factor; D011987:Receptors, Steroid; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D051544:Cytochrome P-450 CYP3A; D005966:Glucuronidase; D000090265:Klotho Proteins