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

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

doi:10.1016/j.celrep.2022.111940

Cited by 16 publications

(36 citation statements)

References 109 publications

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“…The amino acid sequences of PNPLA6 and PNPLA7 are ~60% identical, with the N-terminal side facing the endoplasmic reticulum (ER) across the transmembrane domain and the C-terminal side including the catalytic patatin domain facing the cytosol ( Figure 1 ). PNPLA7 displays lysophospholipase activity, hydrolyzing the sn -1 or sn -2 ester of LPC, although it does not catalyze the hydrolysis of PC via PLA 1 /PLA 2 activity [ 13 , 14 ]. Both PNPLA6 and PNPLA7 are widely expressed in various tissues, with PNPLA6 being abundantly expressed in the central nervous system and PNPLA7 in metabolically active tissues including skeletal muscle, liver, and adipose tissue [ 14 ].…”

Section: Properties Of Pnpla7 the Closest Paralog Of Pnpla6mentioning

confidence: 99%

“…PNPLA7 displays lysophospholipase activity, hydrolyzing the sn -1 or sn -2 ester of LPC, although it does not catalyze the hydrolysis of PC via PLA 1 /PLA 2 activity [ 13 , 14 ]. Both PNPLA6 and PNPLA7 are widely expressed in various tissues, with PNPLA6 being abundantly expressed in the central nervous system and PNPLA7 in metabolically active tissues including skeletal muscle, liver, and adipose tissue [ 14 ]. Expression of PNPLA7, but not PNPLA6, is upregulated in the liver and adipose tissue during fasting, suggesting its nutritional regulation [ 14 ].…”

Section: Properties Of Pnpla7 the Closest Paralog Of Pnpla6mentioning

confidence: 99%

“…Both PNPLA6 and PNPLA7 are widely expressed in various tissues, with PNPLA6 being abundantly expressed in the central nervous system and PNPLA7 in metabolically active tissues including skeletal muscle, liver, and adipose tissue [ 14 ]. Expression of PNPLA7, but not PNPLA6, is upregulated in the liver and adipose tissue during fasting, suggesting its nutritional regulation [ 14 ]. In 3T3-L1 adipocytes, expression of PNPLA7 is downregulated by insulin [ 13 ].…”

Section: Properties Of Pnpla7 the Closest Paralog Of Pnpla6mentioning

confidence: 99%

“…In our ongoing efforts to clarify the biological roles of the PLA 2 family by gene targeting [ 17 , 18 , 19 , 20 ], we have recently uncovered a previously unrecognized role of PNPLA7 as a bona fide lysophospholipase in the liver [ 14 ]. The main physiological role of the lysophospholipase PNPLA7 is not merely to remove otherwise toxic LPC when accumulated in excess or to modulate lysophospholipid mediator signaling, but rather to generate glycerophosphocholine (GPC), a hydrolytic product of LPC, as a precursor of free choline, whose labile methyl groups are then preferentially fluxed into the methionine cycle ( Figure 2 ).…”

Section: Properties Of Pnpla7 the Closest Paralog Of Pnpla6mentioning

confidence: 99%

“…PNPLA7 deficiency markedly decreases the mobilization of GPC and choline from membrane PC in the liver, leading to the phenotypes reminiscent of methionine insufficiency. Moreover, striking phenotypic similarity between Pnpla7 −/− and Pnpla8 −/− mice has revealed that PNPLA8 (also known as group VIB PLA 2 or iPLA 2 γ), by regulating the conversion of PC to LPC as a PLA 1 /PLA 2 , lies upstream of PNPLA7 in the hepatic PC-catabolic pathway to mobilize endogenous choline [ 14 ] ( Figure 2 ).…”

Section: Choline/methionine Metabolismmentioning

confidence: 99%

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The Lysophospholipase PNPLA7 Controls Hepatic Choline and Methionine Metabolism

et al. 2023

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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.

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Section: Properties Of Pnpla7 the Closest Paralog Of Pnpla6mentioning

confidence: 99%