Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, NJ, 08854, USA.
Nat Commun. 2018 Feb 7;9(1):540. doi: 10.1038/s41467-018-03060-y.
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.
磷脂酰胆碱（PC）和 S-腺苷甲硫氨酸（SAM）是肝脏脂质水平的关键决定因素，但它们的水平如何调节尚不清楚。在这里，我们表明，调节 PC/SAM 水平的关键一碳循环基因 Pemt 和 Gnmt 在进食后下调，导致 PC 降低和 SAM 升高，但这些效应在小异二聚体伴侣（SHP）缺失或 FGF15 缺失小鼠中减弱。此外，胰岛素/PKB 信号在早期进食状态下将芳香烃受体（AhR）易位到细胞核，并诱导 Pemt 和 Gnmt 的表达。这种诱导在晚期进食状态下被 FGF15 信号激活的 SHP 阻断。肥胖小鼠中腺病毒介导的 AhR 表达增加 PC 水平并加剧脂肪变性，这些效应在 SHP 共表达或 Pemt 下调时减弱。单纯性脂肪变性患者的 PEMT、AHR 和 PC 水平升高，但脂肪性肝炎纤维化患者的 PC 水平显著降低。这项研究确定了 AhR 和 SHP 是 PC/SAM 水平的新的生理调节剂。
