TY - JOUR
T1 - AhR and SHP regulate phosphatidylcholine and S-adenosylmethionine levels in the one-carbon cycle
AU - Kim, Young Chae
AU - Seok, Sunmi
AU - Byun, Sangwon
AU - Kong, Bo
AU - Zhang, Yang
AU - Guo, Grace
AU - Xie, Wen
AU - Ma, Jian
AU - Kemper, Byron
AU - Kemper, Jongsook Kim
N1 - We thank Eric H. Xu for providing recombinant FGF19 and David Moore, Li Wang, and Sayee Anakk for providing SHP-KO mice. We thank the Liver Tissue Procurement and Distribution System of the NIH for providing human liver specimens of NAFLD patients. We also thank Lucas Li, Director of Metabolomics Center at UIUC, for assistance with the LC–MS analysis. This study was supported by an American Heart Association Scientist Development Award (16SDG27570006) to Y.-C.K., an American Heart Association post-doctoral fellowship (17POST33410223) to S.B., and by grants from the National Institutes of Health (DK62777 and DK95842) and the American Diabetes Association (1-16-IBS-156) to J.K.K.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-03060-y
DO - 10.1038/s41467-018-03060-y
M3 - Article
C2 - 29416063
AN - SCOPUS:85041494029
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 540
ER -