Abstract

Phosphatidylcholines (PC) and S-adenosylmethionine (SAM) are critical determinants of hepatic lipid levels, but how their levels are regulated is unclear. Here, we show that Pemt and Gnmt, key one-carbon cycle genes regulating PC/SAM levels, are downregulated after feeding, leading to decreased PC and increased SAM levels, but these effects are blunted in small heterodimer partner (SHP)-null or FGF15-null mice. Further, aryl hydrocarbon receptor (AhR) is translocated into the nucleus by insulin/PKB signaling in the early fed state and induces Pemt and Gnmt expression. This induction is blocked by FGF15 signaling-activated SHP in the late fed state. Adenoviral-mediated expression of AhR in obese mice increases PC levels and exacerbates steatosis, effects that are blunted by SHP co-expression or Pemt downregulation. PEMT, AHR, and PC levels are elevated in simple steatosis patients, but PC levels are robustly reduced in steatohepatitis-fibrosis patients. This study identifies AhR and SHP as new physiological regulators of PC/SAM levels.

Details

Title
AhR and SHP regulate phosphatidylcholine and S-adenosylmethionine levels in the one-carbon cycle
Author
Young-Chae, Kim 1 ; Sunmi Seok 1 ; Byun, Sangwon 1 ; Kong, Bo 2   VIAFID ORCID Logo  ; Zhang, Yang 3 ; Guo, Grace 2 ; Xie, Wen 4 ; Ma, Jian 3 ; Kemper, Byron 1 ; Jongsook Kim Kemper 1 

 Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA 
 Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, NJ, USA 
 Department of Computational and Comparative Genomics Lab, School of Computer Science, Carnegie Melon University, Pittsburgh, PA, USA 
 Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA 
Pages
1-13
Publication year
2018
Publication date
Feb 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1999178237
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.