Cell Reports (Feb 2023)
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 Kiyonari,
- Kohji Kasahara,
- Toshiki Aiba,
- Kazutaka Ikeda,
- Tomoyoshi Soga,
- Makoto Kurano,
- Yutaka Yatomi,
- Makoto Murakami
Affiliations
- Tetsuya Hirabayashi
- Laboratory of Biomembrane, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; Lipid Metabolism Project, Department of Advanced Science for Biomolecules, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; Corresponding author
- Mai Kawaguchi
- Laboratory of Biomembrane, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; Laboratory of Microenvironmental Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
- Sayaka Harada
- Laboratory of Microenvironmental Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
- Misa Mouri
- Lipid Metabolism Project, Department of Advanced Science for Biomolecules, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; Department of Biology, Faculty of Science, Ochanomizu University, Tokyo 112-8610, Japan
- Rina Takamiya
- Laboratory of Microenvironmental Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
- Yoshimi Miki
- Lipid Metabolism Project, Department of Advanced Science for Biomolecules, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; Laboratory of Microenvironmental Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
- Hiroyasu Sato
- Lipid Metabolism Project, Department of Advanced Science for Biomolecules, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; Laboratory of Microenvironmental Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
- Yoshitaka Taketomi
- Lipid Metabolism Project, Department of Advanced Science for Biomolecules, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; Laboratory of Microenvironmental Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
- Kohei Yokoyama
- Laboratory of Biomembrane, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; Lipid Metabolism Project, Department of Advanced Science for Biomolecules, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
- Tetsuyuki Kobayashi
- Department of Biology, Faculty of Science, Ochanomizu University, Tokyo 112-8610, Japan
- Suzumi M. Tokuoka
- Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
- Yoshihiro Kita
- Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Life Sciences Core Facility, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
- Emiko Yoda
- Division of Health Chemistry, Department of Healthcare and Regulatory Sciences, School of Pharmacy, Showa University, Tokyo 142-8555, Japan
- Shuntaro Hara
- Division of Health Chemistry, Department of Healthcare and Regulatory Sciences, School of Pharmacy, Showa University, Tokyo 142-8555, Japan
- Kyohei Mikami
- Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
- Yasumasa Nishito
- Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
- Norihito Kikuchi
- Laboratory of Biomembrane, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
- Rieko Nakata
- Department of Food Science and Nutrition, Nara Women’s University, Nara, 630-8506, Japan
- Mari Kaneko
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan
- Hiroshi Kiyonari
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan
- Kohji Kasahara
- Laboratory of Biomembrane, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
- Toshiki Aiba
- Laboratory of Microenvironmental Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Department of Radiation Effects Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
- Kazutaka Ikeda
- Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan
- Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
- Makoto Kurano
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo 113-8655, Japan
- Yutaka Yatomi
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo 113-8655, Japan
- Makoto Murakami
- Lipid Metabolism Project, Department of Advanced Science for Biomolecules, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; Laboratory of Microenvironmental Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan; Corresponding author
- Journal volume & issue
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Vol. 42,
no. 2
p. 111940
Abstract
Summary: 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.
