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

Tetsuya Hirabayashi¹, Mai Kawaguchi², Sayaka Harada³, Misa Mouri⁴, Rina Takamiya³, Yoshimi Miki⁵, Hiroyasu Sato⁵, Yoshitaka Taketomi⁵, Kohei Yokoyama⁶, Tetsuyuki Kobayashi⁷, Suzumi M Tokuoka⁸, Yoshihiro Kita⁹, Emiko Yoda¹⁰, Shuntaro Hara¹⁰, Kyohei Mikami¹¹, Yasumasa Nishito¹¹, Norihito Kikuchi¹², Rieko Nakata¹³, Mari Kaneko¹⁴, Hiroshi Kiyonari¹⁴, Kohji Kasahara¹², Toshiki Aiba¹⁵, Kazutaka Ikeda¹⁶, Tomoyoshi Soga¹⁷, Makoto Kurano¹⁸, Yutaka Yatomi¹⁸, Makoto Murakami¹⁹

Affiliations

¹ 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. Electronic address: hirabayashi-tt@igakuken.or.jp.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ Department of Biology, Faculty of Science, Ochanomizu University, Tokyo 112-8610, Japan.
⁸ Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
⁹ 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.
¹⁰ Division of Health Chemistry, Department of Healthcare and Regulatory Sciences, School of Pharmacy, Showa University, Tokyo 142-8555, Japan.
¹¹ Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
¹² Laboratory of Biomembrane, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
¹³ Department of Food Science and Nutrition, Nara Women's University, Nara, 630-8506, Japan.
¹⁴ Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan.
¹⁵ 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.
¹⁶ Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan.
¹⁷ Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan.
¹⁸ Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
¹⁹ 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. Electronic address: makmurak@m.u-tokyo.ac.jp.

PMID: 36719796
DOI: 10.1016/j.celrep.2022.111940

Free article

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

Tetsuya Hirabayashi et al. Cell Rep. 2023.

Free article

. 2023 Feb 28;42(2):111940.

doi: 10.1016/j.celrep.2022.111940. Epub 2023 Jan 30.

Authors

Affiliations

¹ 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. Electronic address: hirabayashi-tt@igakuken.or.jp.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ Department of Biology, Faculty of Science, Ochanomizu University, Tokyo 112-8610, Japan.
⁸ Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
⁹ 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.
¹⁰ Division of Health Chemistry, Department of Healthcare and Regulatory Sciences, School of Pharmacy, Showa University, Tokyo 142-8555, Japan.
¹¹ Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
¹² Laboratory of Biomembrane, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
¹³ Department of Food Science and Nutrition, Nara Women's University, Nara, 630-8506, Japan.
¹⁴ Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan.
¹⁵ 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.
¹⁶ Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan.
¹⁷ Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan.
¹⁸ Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
¹⁹ 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. Electronic address: makmurak@m.u-tokyo.ac.jp.

PMID: 36719796
DOI: 10.1016/j.celrep.2022.111940

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.

Keywords: CP: Metabolism; PNPLA; choline; glycerophosphocholine; liver; lysophospholipase; metabolism; methionine; methyl group; phospholipase; phospholipid.

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Declaration of interests The authors declare no competing interests.

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

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

Authors

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Abstract

Conflict of interest statement

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