title: Thyroid hormone receptor regulates most genes independently of fibroblast growth factor 21 in liver.
abstract: Thyroid hormone (TH) acts through specific receptors (TRs), which are conditional transcription factors, to induce fibroblast growth factor 21 (FGF21), a peptide hormone that is usually induced by fasting and that influences lipid and carbohydrate metabolism via local hepatic and systemic endocrine effects. While TH and FGF21 display overlapping actions when administered, including reductions in serum lipids, according to the current models these hormones act independently in vivo. In this study, we examined mechanisms of regulation of FGF21 expression by TH and tested the possibility that FGF21 is required for induction of hepatic TH-responsive genes. We confirm that active TH (triiodothyronine (T3)) and the TRβ-selective thyromimetic GC1 increase FGF21 transcript and peptide levels in mouse liver and that this effect requires TRβ. T3 also induces FGF21 in cultured hepatocytes and this effect involves direct actions of TRβ1, which binds a TRE within intron 2 of FGF21. Gene expression profiles of WT and Fgf21-knockout mice are very similar, indicating that FGF21 is dispensable for the majority of hepatic T3 gene responses. A small subset of genes displays diminished T3 response in the absence of FGF21. However, most of these are not obviously directly involved in T3-dependent hepatic metabolic processes. Consistent with these results, T3-dependent effects on serum cholesterol are maintained in the Fgf21(-/-) background and we observe no effect of the Fgf21-knockout background on serum triglycerides and glucose. Our findings indicate that T3 regulates the genes involved in classical hepatic metabolic responses independently of FGF21.
authors.affiliation: Houston Methodist Research InstituteGenomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USACollege of Arts and SciencesChemistry Department, Indiana University Bloomington, Bloomington, Indiana, USADepartments of PaediatricsOncology, and Physiology and Pharmacology, University of Western Ontario, London, Ontario, CanadaChildren's Health Research InstituteLondon, Ontario, CanadaDepartment of Molecular Physiology and BiophysicsBaylor College of Medicine, Houston, Texas, USAThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou, China.
authors.forename: Aijun
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Houston Methodist Research InstituteGenomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USACollege of Arts and SciencesChemistry Department, Indiana University Bloomington, Bloomington, Indiana, USADepartments of PaediatricsOncology, and Physiology and Pharmacology, University of Western Ontario, London, Ontario, CanadaChildren's Health Research InstituteLondon, Ontario, CanadaDepartment of Molecular Physiology and BiophysicsBaylor College of Medicine, Houston, Texas, USAThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou, China.
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Sieglaff
authors.affiliation: Houston Methodist Research InstituteGenomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USACollege of Arts and SciencesChemistry Department, Indiana University Bloomington, Bloomington, Indiana, USADepartments of PaediatricsOncology, and Physiology and Pharmacology, University of Western Ontario, London, Ontario, CanadaChildren's Health Research InstituteLondon, Ontario, CanadaDepartment of Molecular Physiology and BiophysicsBaylor College of Medicine, Houston, Texas, USAThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou, China.
authors.forename: Jean Philippe
authors.initials: JP
authors.lastname: York
authors.affiliation: Houston Methodist Research InstituteGenomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USACollege of Arts and SciencesChemistry Department, Indiana University Bloomington, Bloomington, Indiana, USADepartments of PaediatricsOncology, and Physiology and Pharmacology, University of Western Ontario, London, Ontario, CanadaChildren's Health Research InstituteLondon, Ontario, CanadaDepartment of Molecular Physiology and BiophysicsBaylor College of Medicine, Houston, Texas, USAThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou, China.
authors.forename: Ji Ho
authors.initials: JH
authors.lastname: Suh
authors.affiliation: Houston Methodist Research InstituteGenomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USACollege of Arts and SciencesChemistry Department, Indiana University Bloomington, Bloomington, Indiana, USADepartments of PaediatricsOncology, and Physiology and Pharmacology, University of Western Ontario, London, Ontario, CanadaChildren's Health Research InstituteLondon, Ontario, CanadaDepartment of Molecular Physiology and BiophysicsBaylor College of Medicine, Houston, Texas, USAThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou, China.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Ayers
authors.affiliation: Houston Methodist Research InstituteGenomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USACollege of Arts and SciencesChemistry Department, Indiana University Bloomington, Bloomington, Indiana, USADepartments of PaediatricsOncology, and Physiology and Pharmacology, University of Western Ontario, London, Ontario, CanadaChildren's Health Research InstituteLondon, Ontario, CanadaDepartment of Molecular Physiology and BiophysicsBaylor College of Medicine, Houston, Texas, USAThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou, China.
authors.forename: Glenn E
authors.initials: GE
authors.lastname: Winnier
authors.affiliation: Houston Methodist Research InstituteGenomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USACollege of Arts and SciencesChemistry Department, Indiana University Bloomington, Bloomington, Indiana, USADepartments of PaediatricsOncology, and Physiology and Pharmacology, University of Western Ontario, London, Ontario, CanadaChildren's Health Research InstituteLondon, Ontario, CanadaDepartment of Molecular Physiology and BiophysicsBaylor College of Medicine, Houston, Texas, USAThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou, China.
authors.forename: Alexei
authors.initials: A
authors.lastname: Kharitonenkov
authors.affiliation: Houston Methodist Research InstituteGenomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USACollege of Arts and SciencesChemistry Department, Indiana University Bloomington, Bloomington, Indiana, USADepartments of PaediatricsOncology, and Physiology and Pharmacology, University of Western Ontario, London, Ontario, CanadaChildren's Health Research InstituteLondon, Ontario, CanadaDepartment of Molecular Physiology and BiophysicsBaylor College of Medicine, Houston, Texas, USAThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou, China Houston Methodist Research InstituteGenomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USACollege of Arts and SciencesChemistry Department, Indiana University Bloomington, Bloomington, Indiana, USADepartments of PaediatricsOncology, and Physiology and Pharmacology, University of Western Ontario, London, Ontario, CanadaChildren's Health Research InstituteLondon, Ontario, CanadaDepartment of Molecular Physiology and BiophysicsBaylor College of Medicine, Houston, Texas, USAThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou, China.
authors.forename: Christopher
authors.initials: C
authors.lastname: Pin
authors.affiliation: Houston Methodist Research InstituteGenomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USACollege of Arts and SciencesChemistry Department, Indiana University Bloomington, Bloomington, Indiana, USADepartments of PaediatricsOncology, and Physiology and Pharmacology, University of Western Ontario, London, Ontario, CanadaChildren's Health Research InstituteLondon, Ontario, CanadaDepartment of Molecular Physiology and BiophysicsBaylor College of Medicine, Houston, Texas, USAThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou, China.
authors.forename: Pumin
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Houston Methodist Research InstituteGenomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USACollege of Arts and SciencesChemistry Department, Indiana University Bloomington, Bloomington, Indiana, USADepartments of PaediatricsOncology, and Physiology and Pharmacology, University of Western Ontario, London, Ontario, CanadaChildren's Health Research InstituteLondon, Ontario, CanadaDepartment of Molecular Physiology and BiophysicsBaylor College of Medicine, Houston, Texas, USAThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou, China xxia2@tmhs.org pwebb@tmhs.org.
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.affiliation: Houston Methodist Research InstituteGenomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USACollege of Arts and SciencesChemistry Department, Indiana University Bloomington, Bloomington, Indiana, USADepartments of PaediatricsOncology, and Physiology and Pharmacology, University of Western Ontario, London, Ontario, CanadaChildren's Health Research InstituteLondon, Ontario, CanadaDepartment of Molecular Physiology and BiophysicsBaylor College of Medicine, Houston, Texas, USAThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou, China Houston Methodist Research InstituteGenomic Medicine Program, 6670 Bertner Ave, Houston, Texas 77030, USACollege of Arts and SciencesChemistry Department, Indiana University Bloomington, Bloomington, Indiana, USADepartments of PaediatricsOncology, and Physiology and Pharmacology, University of Western Ontario, London, Ontario, CanadaChildren's Health Research InstituteLondon, Ontario, CanadaDepartment of Molecular Physiology and BiophysicsBaylor College of Medicine, Houston, Texas, USAThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou, China xxia2@tmhs.org pwebb@tmhs.org.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Xia
mesh_terms: D000818:Animals; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D020218:Response Elements; D037042:Thyroid Hormone Receptors beta / Q000502:physiology*; D014284:Triiodothyronine / Q000494:pharmacology
chemical_list: D037042:Thyroid Hormone Receptors beta; C414620:fibroblast growth factor 21; D014284:Triiodothyronine; D005346:Fibroblast Growth Factors
keywords: FGF; gene expression; metabolism; nuclear receptor