The Lysophospholipase PNPLA7 Controls Hepatic Choline and Methionine Metabolism
Sayaka Harada,
Yoshitaka Taketomi,
Toshiki Aiba,
Mai Kawaguchi,
Tetsuya Hirabayashi,
Baasanjav Uranbileg,
Makoto Kurano,
Yutaka Yatomi,
Makoto Murakami
Affiliations
Sayaka Harada
Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
Yoshitaka Taketomi
Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
Toshiki Aiba
Department of Radiation Effects Research, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
Mai Kawaguchi
Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
Tetsuya Hirabayashi
Laboratory of Biomembrane, Department of Basic Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
Baasanjav Uranbileg
Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo 113-8655, 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
Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
The in vivo roles of lysophospholipase, which cleaves a fatty acyl ester of lysophospholipid, remained unclear. Recently, we have unraveled a previously unrecognized physiological role of the lysophospholipase PNPLA7, a member of the Ca2+-independent phospholipase A2 (iPLA2) family, as a key regulator of the production of glycerophosphocholine (GPC), a precursor of endogenous choline, whose methyl groups are preferentially fluxed into the methionine cycle in the liver. PNPLA7 deficiency in mice markedly decreases hepatic GPC, choline, and several metabolites related to choline/methionine metabolism, leading to various symptoms reminiscent of methionine shortage. Overall metabolic alterations in the liver of Pnpla7-null mice in vivo largely recapitulate those in methionine-deprived hepatocytes in vitro. Reduction of the methyl donor S-adenosylmethionine (SAM) after methionine deprivation decreases the methylation of the PNPLA7 gene promoter, relieves PNPLA7 expression, and thereby increases GPC and choline levels, likely as a compensatory adaptation. In line with the view that SAM prevents the development of liver cancer, the expression of PNPLA7, as well as several enzymes in the choline/methionine metabolism, is reduced in human hepatocellular carcinoma. These findings uncover an unexplored role of a lysophospholipase in hepatic phospholipid catabolism coupled with choline/methionine metabolism.
