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.