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

doi:10.1016/j.celrep.2022.111940

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

Graduate School of Media and Governance

Research output: Contribution to journal › Article › peer-review

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 language	English
Article number	111940
Journal	Cell Reports
Volume	42
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2022.111940
Publication status	Published - 2023 Feb 28

Keywords

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

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2022.111940

Cite this

Hirabayashi, T., Kawaguchi, M., Harada, S., Mouri, M., Takamiya, R., Miki, Y., Sato, H., Taketomi, Y., Yokoyama, K., Kobayashi, T., Tokuoka, S. M., Kita, Y., Yoda, E., Hara, S., Mikami, K., Nishito, Y., Kikuchi, N., Nakata, R., Kaneko, M., ... Murakami, M. (2023). Hepatic phosphatidylcholine catabolism driven by PNPLA7 and PNPLA8 supplies endogenous choline to replenish the methionine cycle with methyl groups. Cell Reports, 42(2), [111940]. https://doi.org/10.1016/j.celrep.2022.111940

Hirabayashi, T, Kawaguchi, M, Harada, S, Mouri, M, Takamiya, R, Miki, Y, Sato, H, Taketomi, Y, Yokoyama, K, Kobayashi, T, Tokuoka, SM, Kita, Y, Yoda, E, Hara, S, Mikami, K, Nishito, Y, Kikuchi, N, Nakata, R, Kaneko, M, Kiyonari, H, Kasahara, K, Aiba, T, Ikeda, K, Soga, T, Kurano, M, Yatomi, Y & Murakami, M 2023, 'Hepatic phosphatidylcholine catabolism driven by PNPLA7 and PNPLA8 supplies endogenous choline to replenish the methionine cycle with methyl groups', Cell Reports, vol. 42, no. 2, 111940. https://doi.org/10.1016/j.celrep.2022.111940

@article{7d7aa5dee3d14cf7b7a889c8fafce688,

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

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",

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

note = "Funding Information: We thank Toru Shimamura, Masataka Ohta, and Drs. Hisae Sumi-Akamaru (Higashiosaka City Medical Center), Satoru Kawamura, Shigeyuki Kurosaki, Motoyuki Ohtsuka (The University of Tokyo), and Yu-Shin Sou (Juntendo University) for technical assistance; Drs. Koei Shinzawa (Osaka University) and Takao Shimizu (National Center for Global Health and Medicine) for providing Pnpla9 −/− and Pla2g4a −/− mice, respectively; and Drs. Seiichiro Ohsako (The University of Tokyo), Takeshi Ohkubo (Sendai Shirayuri Woman{\textquoteright}s College), and Hidehiko Hibino (Japan Society for Lipid Nutrition) for helpful discussions. This work was supported by Grants-in-Aid for Scientific Research JP15H05905 , JP16H02613 , JP18H05025 , JP19K22483 , and JP20H05691 (to M.M.); 24590367 , JP15K15094 , and JP18K06978 (to T.H.) from the Japan Society for the Promotion of Science ; and AMED-CREST JP18gm0710006 and JP22gm1210013 (to M.M.) and FORCE JP19gm4010005h (to M.M.) from the Japan Agency for Medical Research and Development . Funding Information: We thank Toru Shimamura, Masataka Ohta, and Drs. Hisae Sumi-Akamaru (Higashiosaka City Medical Center), Satoru Kawamura, Shigeyuki Kurosaki, Motoyuki Ohtsuka (The University of Tokyo), and Yu-Shin Sou (Juntendo University) for technical assistance; Drs. Koei Shinzawa (Osaka University) and Takao Shimizu (National Center for Global Health and Medicine) for providing Pnpla9−/− and Pla2g4a−/− mice, respectively; and Drs. Seiichiro Ohsako (The University of Tokyo), Takeshi Ohkubo (Sendai Shirayuri Woman's College), and Hidehiko Hibino (Japan Society for Lipid Nutrition) for helpful discussions. This work was supported by Grants-in-Aid for Scientific Research JP15H05905, JP16H02613, JP18H05025, JP19K22483, and JP20H05691 (to M.M.); 24590367, JP15K15094, and JP18K06978 (to T.H.) from the Japan Society for the Promotion of Science; and AMED-CREST JP18gm0710006 and JP22gm1210013 (to M.M.) and FORCE JP19gm4010005h (to M.M.) from the Japan Agency for Medical Research and Development. T.H. and M. Murakami conceived the study and wrote the manuscript. M. Kaneko and H.K. performed gene targeting. T.H. M. Kawaguchi, S. Harada, M. Mouri, R.T. H.S. E.Y. and S. Hara analyzed Pnpla7−/− and Pnpla8−/− mice and cultured cells. K.Y. helped with the baculovirus experiments. Y.M. R.N. S.M. T. Y.K. N.K. K.I. and T.S. performed the metabolome analysis. Y.N. performed the microarray analysis. K.M. performed electron microscopy. M. Kurano, Y.Y. Y.T. T.K. K.K. and T.A. provided expert advice. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2023",

month = feb,

day = "28",

doi = "10.1016/j.celrep.2022.111940",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - Hepatic phosphatidylcholine catabolism driven by PNPLA7 and PNPLA8 supplies endogenous choline to replenish the methionine cycle with methyl groups

AU - Hirabayashi, Tetsuya

AU - Kawaguchi, Mai

AU - Harada, Sayaka

AU - Mouri, Misa

AU - Takamiya, Rina

AU - Miki, Yoshimi

AU - Sato, Hiroyasu

AU - Taketomi, Yoshitaka

AU - Yokoyama, Kohei

AU - Kobayashi, Tetsuyuki

AU - Tokuoka, Suzumi M.

AU - Kita, Yoshihiro

AU - Yoda, Emiko

AU - Hara, Shuntaro

AU - Mikami, Kyohei

AU - Nishito, Yasumasa

AU - Kikuchi, Norihito

AU - Nakata, Rieko

AU - Kaneko, Mari

AU - Kiyonari, Hiroshi

AU - Kasahara, Kohji

AU - Aiba, Toshiki

AU - Ikeda, Kazutaka

AU - Soga, Tomoyoshi

AU - Kurano, Makoto

AU - Yatomi, Yutaka

AU - Murakami, Makoto

N1 - Funding Information: We thank Toru Shimamura, Masataka Ohta, and Drs. Hisae Sumi-Akamaru (Higashiosaka City Medical Center), Satoru Kawamura, Shigeyuki Kurosaki, Motoyuki Ohtsuka (The University of Tokyo), and Yu-Shin Sou (Juntendo University) for technical assistance; Drs. Koei Shinzawa (Osaka University) and Takao Shimizu (National Center for Global Health and Medicine) for providing Pnpla9 −/− and Pla2g4a −/− mice, respectively; and Drs. Seiichiro Ohsako (The University of Tokyo), Takeshi Ohkubo (Sendai Shirayuri Woman’s College), and Hidehiko Hibino (Japan Society for Lipid Nutrition) for helpful discussions. This work was supported by Grants-in-Aid for Scientific Research JP15H05905 , JP16H02613 , JP18H05025 , JP19K22483 , and JP20H05691 (to M.M.); 24590367 , JP15K15094 , and JP18K06978 (to T.H.) from the Japan Society for the Promotion of Science ; and AMED-CREST JP18gm0710006 and JP22gm1210013 (to M.M.) and FORCE JP19gm4010005h (to M.M.) from the Japan Agency for Medical Research and Development . Funding Information: We thank Toru Shimamura, Masataka Ohta, and Drs. Hisae Sumi-Akamaru (Higashiosaka City Medical Center), Satoru Kawamura, Shigeyuki Kurosaki, Motoyuki Ohtsuka (The University of Tokyo), and Yu-Shin Sou (Juntendo University) for technical assistance; Drs. Koei Shinzawa (Osaka University) and Takao Shimizu (National Center for Global Health and Medicine) for providing Pnpla9−/− and Pla2g4a−/− mice, respectively; and Drs. Seiichiro Ohsako (The University of Tokyo), Takeshi Ohkubo (Sendai Shirayuri Woman's College), and Hidehiko Hibino (Japan Society for Lipid Nutrition) for helpful discussions. This work was supported by Grants-in-Aid for Scientific Research JP15H05905, JP16H02613, JP18H05025, JP19K22483, and JP20H05691 (to M.M.); 24590367, JP15K15094, and JP18K06978 (to T.H.) from the Japan Society for the Promotion of Science; and AMED-CREST JP18gm0710006 and JP22gm1210013 (to M.M.) and FORCE JP19gm4010005h (to M.M.) from the Japan Agency for Medical Research and Development. T.H. and M. Murakami conceived the study and wrote the manuscript. M. Kaneko and H.K. performed gene targeting. T.H. M. Kawaguchi, S. Harada, M. Mouri, R.T. H.S. E.Y. and S. Hara analyzed Pnpla7−/− and Pnpla8−/− mice and cultured cells. K.Y. helped with the baculovirus experiments. Y.M. R.N. S.M. T. Y.K. N.K. K.I. and T.S. performed the metabolome analysis. Y.N. performed the microarray analysis. K.M. performed electron microscopy. M. Kurano, Y.Y. Y.T. T.K. K.K. and T.A. provided expert advice. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: © 2022 The Author(s)

PY - 2023/2/28

Y1 - 2023/2/28

N2 - 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.

AB - 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.

KW - CP: Metabolism

KW - PNPLA

KW - choline

KW - glycerophosphocholine

KW - liver

KW - lysophospholipase

KW - metabolism

KW - methionine

KW - methyl group

KW - phospholipase

KW - phospholipid

UR - http://www.scopus.com/inward/record.url?scp=85147226576&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85147226576&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2022.111940

DO - 10.1016/j.celrep.2022.111940

M3 - Article

C2 - 36719796

AN - SCOPUS:85147226576

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 2

M1 - 111940

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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