Hepatic phosphatidylcholine catabolism driven by PNPLA7 and PNPLA8 supplies endogenous choline to replenish the methionine cycle with methyl groups

Tetsuya Hirabayashi, Mai Kawaguchi, Sayaka Harada, Misa Mouri, Rina Takamiya, Yoshimi Miki, Hiroyasu Sato, Yoshitaka Taketomi, Kohei Yokoyama, Tetsuyuki Kobayashi, Suzumi M. Tokuoka, Yoshihiro Kita, Emiko Yoda, Shuntaro Hara, Kyohei Mikami, Yasumasa Nishito, Norihito Kikuchi, Rieko Nakata, Mari Kaneko, Hiroshi KiyonariKohji Kasahara, Toshiki Aiba, Kazutaka Ikeda, Tomoyoshi Soga, Makoto Kurano, Yutaka Yatomi, Makoto Murakami

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

Choline supplies methyl groups for regeneration of methionine and the methyl donor S-adenosylmethionine in the liver. Here, we report that the catabolism of membrane phosphatidylcholine (PC) into water-soluble glycerophosphocholine (GPC) by the phospholipase/lysophospholipase PNPLA8-PNPLA7 axis enables endogenous choline stored in hepatic PC to be utilized in methyl metabolism. PNPLA7-deficient mice show marked decreases in hepatic GPC, choline, and several metabolites related to the methionine cycle, accompanied by various signs of methionine insufficiency, including growth retardation, hypoglycemia, hypolipidemia, increased energy consumption, reduced adiposity, increased fibroblast growth factor 21 (FGF21), and an altered histone/DNA methylation landscape. Moreover, PNPLA8-deficient mice recapitulate most of these phenotypes. In contrast to wild-type mice fed a methionine/choline-deficient diet, both knockout strains display decreased hepatic triglyceride, likely via reductions of lipogenesis and GPC-derived glycerol flux. Collectively, our findings highlight the biological importance of phospholipid catabolism driven by PNPLA8/PNPLA7 in methyl group flux and triglyceride synthesis in the liver.

Original languageEnglish
Article number111940
JournalCell Reports
Volume42
Issue number2
DOIs
Publication statusPublished - 2023 Feb 28

Keywords

  • CP: Metabolism
  • PNPLA
  • choline
  • glycerophosphocholine
  • liver
  • lysophospholipase
  • metabolism
  • methionine
  • methyl group
  • phospholipase
  • phospholipid

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology

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