The Lysophospholipase PNPLA7 Controls Hepatic Choline and Methionine Metabolism

Abstract

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.

The glycerophosphocholine acyltransferase Gpc1 contributes to phosphatidylcholine biosynthesis, long-term viability, and embedded hyphal growth in Candida albicans

“…Given that the kidney is a site of disseminated candidiasis ( 45 ), it is noteworthy that GPC is also a renal osmolyte reported to be present in renal cells at roughly 18 nmoles/mg protein ( 46 , 47 , 48 , 49 ). The GPC content in other host microenvironments is unknown and likely dynamic, because GPC is liberated through phospholipase-mediated PC hydrolysis ( 50 , 51 , 52 ).…”

Glycerophosphocholine provision rescues Candida albicans growth and signaling phenotypes associated with phosphate limitation

“…Although quantitative metabolomic data on GPC are limited, it is clear that serum P i (at roughly 1 mM [ 26 , 27 ]) is more abundant than serum GPC ( 19 , 25 ). However, the relative concentrations of GPC and P i in host microenvironments have not been established and are undoubtedly dynamic, as GPC is liberated through phospholipase-mediated PC hydrolysis, during which it may reach higher concentrations than those found in serum at a steady state, while serum and cytosolic P i concentrations are highly regulated ( 17 , 46 , 47 ). Both phospholipase B1 and B5 are required for full virulence of C. albicans .…”

Lysophosphatidylserine: A Signaling Lipid with Implications in Human Diseases

“…The patatin-like phospholipase domain containing protein no. 7 (PNPLA7) is another candidate mammalian enzyme that possesses a general lysophospholipase activity. − In mammals, PNPLA7 is a 150 kDa (∼1300 amino acids) ER-resident integral membrane enzyme from the mSH family that shows expression and activity only in the metabolic active tissues (primarily liver and kidneys, and to a lesser extent in the lungs) (UniProt ID: Q6ZV29 for human PNPLA7). ,, Recent in vitro biochemical studies have shown that PNPLA7 has robust lysophospholipase activity against several lysophospholipid substrates, including lyso-PS . Overexpression of PNPLA7 activity in mammalian COS-7 cells results in decreased production of several lysophospholipids, including lyso-PS .…”