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 and Jongsook Kim Kemper ()
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Young-Chae Kim: University of Illinois at Urbana-Champaign
Sunmi Seok: University of Illinois at Urbana-Champaign
Sangwon Byun: University of Illinois at Urbana-Champaign
Bo Kong: Rutgers University
Yang Zhang: Carnegie Melon University
Grace Guo: Rutgers University
Wen Xie: University of Pittsburgh
Jian Ma: Carnegie Melon University
Byron Kemper: University of Illinois at Urbana-Champaign
Jongsook Kim Kemper: University of Illinois at Urbana-Champaign

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03060-y

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