AhR and SHP regulate phosphatidylcholine and S-adenosylmethionine levels in the one-carbon cycle

Young-Chae Kim; Sunmi Seok; Sangwon Byun; Bo Kong; Yang Zhang; Grace Guo; Wen Xie; Jian Ma; Byron Kemper; Jongsook Kim Kemper

doi:10.1038/s41467-018-03060-y

AhR and SHP regulate phosphatidylcholine and S-adenosylmethionine levels in the one-carbon cycle

Nat Commun. 2018 Feb 7;9(1):540. doi: 10.1038/s41467-018-03060-y.

Authors

Young-Chae Kim¹, Sunmi Seok², Sangwon Byun², Bo Kong³, Yang Zhang⁴, Grace Guo³, Wen Xie⁵, Jian Ma⁴, Byron Kemper², Jongsook Kim Kemper⁶

Affiliations

¹ Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA. [email protected].
² Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
³ Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, NJ, 08854, USA.
⁴ Department of Computational and Comparative Genomics Lab, School of Computer Science, Carnegie Melon University, Pittsburgh, PA, 15213, USA.
⁵ Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
⁶ Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carbon Cycle*
Fibroblast Growth Factors / genetics
Fibroblast Growth Factors / metabolism
Fibroblast Growth Factors / pharmacology
Glycine N-Methyltransferase / genetics
Glycine N-Methyltransferase / metabolism
Humans
Liver / metabolism
Male
Mice
Mice, Knockout
Non-alcoholic Fatty Liver Disease / genetics
Non-alcoholic Fatty Liver Disease / metabolism
Phosphatidylcholines / metabolism*
Phosphatidylethanolamine N-Methyltransferase / genetics
Phosphatidylethanolamine N-Methyltransferase / metabolism
Protein Binding / drug effects
Receptors, Aryl Hydrocarbon / genetics
Receptors, Aryl Hydrocarbon / metabolism*
Receptors, Cytoplasmic and Nuclear / genetics
Receptors, Cytoplasmic and Nuclear / metabolism*
S-Adenosylmethionine / metabolism*

Substances

Phosphatidylcholines
Receptors, Aryl Hydrocarbon
Receptors, Cytoplasmic and Nuclear
fibroblast growth factor 15, mouse
nuclear receptor subfamily 0, group B, member 2
Fibroblast Growth Factors
S-Adenosylmethionine
PEMT protein, mouse
Phosphatidylethanolamine N-Methyltransferase
Glycine N-Methyltransferase
Gnmt protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding