title: Hepatic FXR/SHP axis modulates systemic glucose and fatty acid homeostasis in aged mice.
abstract: The nuclear receptors farnesoid X receptor (FXR; NR1H4) and small heterodimer partner (SHP; NR0B2) play crucial roles in bile acid homeostasis. Global double knockout of FXR and SHP signaling (DKO) causes severe cholestasis and liver injury at early ages. Here, we report an unexpected beneficial impact on glucose and fatty acid metabolism in aged DKO mice, which show suppressed body weight gain and adiposity when maintained on normal chow. This phenotype was not observed in single Fxr or Shp knockouts. Liver-specific Fxr/Shp double knockout mice fully phenocopied the DKO mice, with lower hepatic triglyceride accumulation, improved glucose/insulin tolerance, and accelerated fatty acid use. In both DKO and liver-specific Fxr/Shp double knockout livers, these metabolic phenotypes were associated with altered expression of fatty acid metabolism and autophagy-machinery genes. Loss of the hepatic FXR/SHP axis reprogrammed white and brown adipose tissue gene expression to boost fatty acid usage.
  
  
  
  Combined deletion of the hepatic FXR/SHP axis improves glucose/fatty acid homeostasis in aged mice, reversing the aging phenotype of body weight gain, increased adiposity, and glucose/insulin tolerance, suggesting a central role of this axis in whole-body energy homeostasis. (Hepatology 2017;66:498-509).
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.
authors.forename: Kang Ho
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, TX.
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.|Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Jae Man
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Saha
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL.
authors.forename: Sayeepriyadarshini
authors.initials: S
authors.lastname: Anakk
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.|Program in Developmental Biology, Baylor College of Medicine, Houston, TX.|Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX.
authors.forename: David D
authors.identifier: 0000-0002-5151-9748
authors.initials: DD
authors.lastname: Moore
mesh_terms: D000375:Aging / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001343:Autophagy / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics*; D011897:Random Allocation; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D005227:Fatty Acids; D005947:Glucose; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C509248:Ptpn6 protein, mouse