Hepatic FXR/SHP Axis Modulates Systemic Glucose and Fatty Acid Homeostasis in Aged Mice

Presentation Number: OR42-4
Date of Presentation: April 3rd, 2017

Kang Ho Kim*1, Sungwoo Choi2, Ying Zhou1, Eun Young Kim3, Jae Man Lee3, Pradip K Saha1, Sayeepriyadarshini Anakk4 and David D Moore1
1Baylor College of Medicine, Houston, TX, 2Baylor College of Medicine, 3Kyungpook National University, 4University of Illinois, Urbana, IL

Abstract

The nuclear receptors farnesoid X receptor (FXR; NR1H4) and small heterodimer partner (SHP; NR0B2) play crucial roles in bile acid homeostasis. Global disruption of both 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 (FSLKO) mice fully phenocopied the DKO mice, with lower hepatic triglyceride accumulation, improved glucose/insulin tolerance and accelerated fatty acid utilization. In both DKO and FSLKO 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 utilization. In conclusion, 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.

 

Nothing to Disclose: KHK, SC, YZ, EYK, JML, PKS, SA, DDM