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

Cell reports 2023 Feb 28

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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. Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

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. Hepatic phosphatidylcholine catabolism driven by PNPLA7 and PNPLA8 supplies endogenous choline to replenish the methionine cycle with methyl groups. Cell reports. 2023 Feb 28;42(2):111940