FXR Primes the Liver for Intestinal FGF15 Signaling by Transient Induction of β-Klotho.
The bile acid (BA)-sensing nuclear receptor, farnesoid X receptor (FXR), regulates postprandial metabolic responses, including inhibition of BA synthesis, by inducing the intestinal hormone, fibroblast growth factor (FGF)15 (FGF19 in human). In this study, we tested a novel hypothesis that FXR not only induces intestinal FGF15 but also primes the liver for effectively responding to the signal by transcriptional induction of the obligate coreceptor for FGF15, β-Klotho (βKL). Activation of FXR by a synthetic agonist, GW4064, in mice increased occupancy of FXR and its DNA-binding partner, retinoid X receptor-α, at FGF15-signaling component genes, particularly βKL, and induced expression of these genes. Interestingly, mRNA levels of Fgfr4, the FGF15 receptor, were not increased by GW4064, but protein levels increased as a result of βKL-dependent increased protein stability. Both FGF receptor 4 and βKL protein levels were substantially decreased in FXR-knockout (KO) mice, and FGF19 signaling, monitored by phosphorylated ERK, was blunted in FXR-KO mice, FXR-KO mouse hepatocytes, and FXR-down-regulated human hepatocytes. Overexpression of βKL in FXR-lacking hepatocytes partially restored FGF19 signaling and inhibition by FGF19 of Cyp7a1, which encodes the rate-limiting BA biosynthetic enzyme. In mice, transient inductions of intestinal Fgf15 and hepatic βKL were temporally correlated after GW4064 treatment, and pretreatment of hepatocytes with GW4064 before FGF19 treatment enhanced FGF19 signaling, which was abolished by transcriptional inhibition or βKL down-regulation. This study identifies FXR as a gut-liver metabolic coordinator for FGF15/19 action that orchestrates transient induction of hepatic βKL and intestinal Fgf15/19 in a temporally correlated manner.
Department of Molecular and Integrative Physiology (T.F., Y.-C.K., S.B., D.-H.K., S.S., B.K., J.K.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Laboratory of Structure Sciences (K.S.-P., H.E.X.), Van Andel Research Institute, Grand Rapids, Michigan 49503; and Van Andel Research Institute-Shanghai Institute of Materia Medica (H.E.X.), Center for Structure and Function of Drug Targets, Chinese Academy of Sciences-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Ting
T
Fu
Department of Molecular and Integrative Physiology (T.F., Y.-C.K., S.B., D.-H.K., S.S., B.K., J.K.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Laboratory of Structure Sciences (K.S.-P., H.E.X.), Van Andel Research Institute, Grand Rapids, Michigan 49503; and Van Andel Research Institute-Shanghai Institute of Materia Medica (H.E.X.), Center for Structure and Function of Drug Targets, Chinese Academy of Sciences-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Young-Chae
YC
Kim
Department of Molecular and Integrative Physiology (T.F., Y.-C.K., S.B., D.-H.K., S.S., B.K., J.K.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Laboratory of Structure Sciences (K.S.-P., H.E.X.), Van Andel Research Institute, Grand Rapids, Michigan 49503; and Van Andel Research Institute-Shanghai Institute of Materia Medica (H.E.X.), Center for Structure and Function of Drug Targets, Chinese Academy of Sciences-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Sangwon
S
Byun
Department of Molecular and Integrative Physiology (T.F., Y.-C.K., S.B., D.-H.K., S.S., B.K., J.K.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Laboratory of Structure Sciences (K.S.-P., H.E.X.), Van Andel Research Institute, Grand Rapids, Michigan 49503; and Van Andel Research Institute-Shanghai Institute of Materia Medica (H.E.X.), Center for Structure and Function of Drug Targets, Chinese Academy of Sciences-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Dong-Hyun
DH
Kim
Department of Molecular and Integrative Physiology (T.F., Y.-C.K., S.B., D.-H.K., S.S., B.K., J.K.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Laboratory of Structure Sciences (K.S.-P., H.E.X.), Van Andel Research Institute, Grand Rapids, Michigan 49503; and Van Andel Research Institute-Shanghai Institute of Materia Medica (H.E.X.), Center for Structure and Function of Drug Targets, Chinese Academy of Sciences-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Sunmi
S
Seok
Department of Molecular and Integrative Physiology (T.F., Y.-C.K., S.B., D.-H.K., S.S., B.K., J.K.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Laboratory of Structure Sciences (K.S.-P., H.E.X.), Van Andel Research Institute, Grand Rapids, Michigan 49503; and Van Andel Research Institute-Shanghai Institute of Materia Medica (H.E.X.), Center for Structure and Function of Drug Targets, Chinese Academy of Sciences-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Kelly
K
Suino-Powell
Department of Molecular and Integrative Physiology (T.F., Y.-C.K., S.B., D.-H.K., S.S., B.K., J.K.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Laboratory of Structure Sciences (K.S.-P., H.E.X.), Van Andel Research Institute, Grand Rapids, Michigan 49503; and Van Andel Research Institute-Shanghai Institute of Materia Medica (H.E.X.), Center for Structure and Function of Drug Targets, Chinese Academy of Sciences-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
H Eric
HE
Xu
Department of Molecular and Integrative Physiology (T.F., Y.-C.K., S.B., D.-H.K., S.S., B.K., J.K.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Laboratory of Structure Sciences (K.S.-P., H.E.X.), Van Andel Research Institute, Grand Rapids, Michigan 49503; and Van Andel Research Institute-Shanghai Institute of Materia Medica (H.E.X.), Center for Structure and Function of Drug Targets, Chinese Academy of Sciences-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Byron
B
Kemper
Department of Molecular and Integrative Physiology (T.F., Y.-C.K., S.B., D.-H.K., S.S., B.K., J.K.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Laboratory of Structure Sciences (K.S.-P., H.E.X.), Van Andel Research Institute, Grand Rapids, Michigan 49503; and Van Andel Research Institute-Shanghai Institute of Materia Medica (H.E.X.), Center for Structure and Function of Drug Targets, Chinese Academy of Sciences-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Jongsook Kim
JK
Kemper
D000818:Animals; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D007555:Isoxazoles / Q000494:pharmacology; D000090265:Klotho Proteins; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
D005346:Fibroblast Growth Factors; D007555:Isoxazoles; D000090265:Klotho Proteins; D008565:Membrane Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C418622:Klb protein, mouse; C108526:fibroblast growth factor 15, mouse; C412815:GW 4064