title: Bioenergetic cues shift FXR splicing towards FXRα2 to modulate hepatic lipolysis and fatty acid metabolism.
abstract: OBJECTIVE
  Farnesoid X receptor (FXR) plays a prominent role in hepatic lipid metabolism. The FXR gene encodes four proteins with structural differences suggestive of discrete biological functions about which little is known.
  
  
  METHODS
  We expressed each FXR variant in primary hepatocytes and evaluated global gene expression, lipid profile, and metabolic fluxes. Gene delivery of FXR variants to Fxr(-/-) mouse liver was performed to evaluate their role in vivo. The effects of fasting and physical exercise on hepatic Fxr splicing were determined.
  
  
  RESULTS
  We show that FXR splice isoforms regulate largely different gene sets and have specific effects on hepatic metabolism. FXRα2 (but not α1) activates a broad transcriptional program in hepatocytes conducive to lipolysis, fatty acid oxidation, and ketogenesis. Consequently, FXRα2 decreases cellular lipid accumulation and improves cellular insulin signaling to AKT. FXRα2 expression in Fxr(-/-) mouse liver activates a similar gene program and robustly decreases hepatic triglyceride levels. On the other hand, FXRα1 reduces hepatic triglyceride content to a lesser extent and does so through regulation of lipogenic gene expression. Bioenergetic cues, such as fasting and exercise, dynamically regulate Fxr splicing in mouse liver to increase Fxrα2 expression.
  
  
  CONCLUSIONS
  Our results show that the main FXR variants in human liver (α1 and α2) reduce hepatic lipid accumulation through distinct mechanisms and to different degrees. Taking this novel mechanism into account could greatly improve the pharmacological targeting and therapeutic efficacy of FXR agonists.
authors.affiliation: Department of Physiology and Pharmacology, Molecular & Cellular Exercise Physiology Unit, Karolinska Institutet, Stockholm, Sweden; Center for Biomedical Research, University of Algarve, Faro, Portugal.
authors.forename: Jorge C
authors.initials: JC
authors.lastname: Correia
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Julie
authors.initials: J
authors.lastname: Massart
authors.affiliation: Department of Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Jan Freark
authors.initials: JF
authors.lastname: de Boer
authors.affiliation: Department of Physiology and Pharmacology, Molecular & Cellular Exercise Physiology Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Margareta
authors.initials: M
authors.lastname: Porsmyr-Palmertz
authors.affiliation: Department of Physiology and Pharmacology, Molecular & Cellular Exercise Physiology Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vicente
authors.initials: V
authors.lastname: Martínez-Redondo
authors.affiliation: Department of Physiology and Pharmacology, Molecular & Cellular Exercise Physiology Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Leandro Z
authors.initials: LZ
authors.lastname: Agudelo
authors.affiliation: Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Indranil
authors.initials: I
authors.lastname: Sinha
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Meierhofer
authors.affiliation: Center for Biomedical Research, University of Algarve, Faro, Portugal.
authors.forename: Vera
authors.initials: V
authors.lastname: Ribeiro
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Björnholm
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Sauer
authors.affiliation: Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Dahlman-Wright
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
authors.affiliation: Department of Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.affiliation: Department of Physiology and Pharmacology, Molecular & Cellular Exercise Physiology Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Ruas
keywords: Energy metabolism; FXR isoforms; Insulin resistance; NAFLD; Splicing