Lysophospholipase PNPLA7 Controls Hepatic Choline and Methionine Metabolism: Comparison
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The lysophospholipase PNPLA7 is 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. 

  • lysophospholipase
  • phospholipase A2
  • phosphatidylcholine
  • lysophosphatidylcholine
  • glycerophosphocholine
  • S-adenosylmethionine

1. Introduction

The phospholipase A2 (PLA2) superfamily comprises a group of lipolytic enzymes that typically hydrolyze the sn-2 position of glycerophospholipids (phospholipids hereafter) to release fatty acids and lysophospholipids. The mammalian genome encodes more than 50 PLA2s or related enzymes, which are classified into several subfamilies on the basis of their structural and functional properties, including secreted PLA2s (sPLA2s), cytosolic PLA2s (cPLA2s), Ca2+-independent PLA2s (iPLA2s, also called patatin-like phospholipases (PNPLAs)), platelet-activating factor acetylhydrolases (PAF-AHs), lysosomal PLA2 (LPLA2), PLA/acyltransferases (PLAATs), α/β hydrolases (ABHDs), and so on [1]. In general, the PLA2 family has long been implicated in signal transduction by producing lipid mediators derived from polyunsaturated fatty acids (arachidonic acid in particular) and lysophospholipids. However, this principal concept is not sufficient for fully explaining the diverse biological roles of PLA2s, since individual PLA2s display distinct substrate specificities and some of these enzymes catalyze even non-PLA2 reactions, such as phospholipase A1 (PLA1), neutral lipid lipase and transacylase reactions, rendering the understanding of PLA2-driven lipid metabolism to be more complex than previously thought. It has long been considered that the cellular levels of lysophospholipids, a primary PLA2 reaction product, must be tightly controlled through reacylation by acyltransferases or degradation by lysophospholipases, since their unusual accumulation can lead to uncontrolled signaling due to their pleiotropic actions as a class of lipid mediators [2] and can also disturb membrane integrity and even cause cell lysis due to their detergent-like nature [3]. Although several PLA2 enzymes exhibit lysophospholipase activity at least in vitro, the biological importance of this enzymatic reaction in vivo remained largely unclear.
The PNPLA/iPLA2 family contains nine enzymes in humans, which share a patatin domain that was initially discovered in patatin (iPLA2α), a potato protein [1]. In general, enzymes with a large and unique N-terminal region (PNPLA6~9) act on phospholipids, while those lacking the N-terminal domain (PNPLA1~5) act on neutral lipids (Figure 1).
/media/item_content/202303/64266f0a010d6biomolecules-13-00471-g001.png
Figure 1. The PNPLA/iPLA2 family. Structural relationship of PNPLA enzymes (PNPLA1~9), as well as representative disorders caused by knockouts or mutations of these enzymes in mice and humans, are indicated. In principle, PNPLA1~5 act on neutral lipids, while PNPLA6~9 act on phospholipids. The functional association of PNPLA7 and PNPLA8 with hepatic choline/methionine metabolism, is highlighted in red.

2. Properties of PNPLA7, the Closest Paralog of PNPLA6

PNPLA6, also known as neuropathy target esterase (NTE) or iPLA2δ, was originally identified in 1998 as a key factor responsible for organophosphate-induced delayed neuropathy (OPIDN), a neurodegenerative disorder that occurs within a few weeks after exposure to pesticides and nerve agents containing organophosphates [4]. PNPLA6 displays phospholipase B (PLA1/PLA2 + lysophospholipase) activity, hydrolyzing both the sn-1 and sn-2 fatty acyl chains of phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) [5][6][7]. Mutations in the human PNPLA6 gene are linked to rare inherited diseases termed PNPLA6-related disorders, with clinical symptoms including spastic paraplegia, ataxia, hypogonadism, and chorioretinal dystrophy, reminiscent of the OPIDN pathology [8]. PNPLA7, also referred to as NTE-related esterase (NRE) or iPLA2θ, was identified in 2008 as the closest paralog of PNPLA6 [9]. 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 PLA1/PLA2 activity [9][10]. 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 [10]. Expression of PNPLA7, but not PNPLA6, is upregulated in the liver and adipose tissue during fasting, suggesting its nutritional regulation [10]. In 3T3-L1 adipocytes, expression of PNPLA7 is downregulated by insulin [9]. Upon elevated fatty acid flux, the catalytic domain of PNPLA7 targets cellular lipid droplets in response to increased cAMP levels [11]. A recent study has reported that knockdown of hepatic PNPLA7 using adenoviral shRNA delivery impairs the secretion of very low-density lipoprotein (VLDL), proposing that PNPLA7 stabilizes ApoE through protein–protein interaction independent of its lysophospholipase activity [12]. In the ongoing efforts to clarify the biological roles of the PLA2 family by gene targeting [13][14][15][16], scholars have recently uncovered a previously unrecognized role of PNPLA7 as a bona fide lysophospholipase in the liver [10]. 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).
/media/item_content/202303/64266f19a77fcbiomolecules-13-00471-g002.png
Figure 2. An overview of hepatic choline/methionine metabolism. Key metabolites and enzymes in this metabolic pathway are highlighted. Two PNPLA enzymes, PNPLA8 and PNPLA7, contribute sequentially to the mobilization of choline from membrane PC. Methyl groups (CH3) of choline are fluxed into the methionine cycle via betaine. The methionine cycle is coupled with histone and DNA methylation, PC biosynthesis via PEMT, and the folate cycle as another source of methyl group. The PNPLA8/PNPLA7-driven choline is also utilized for PC regeneration through the CDP-choline (Kennedy) pathway, constituting the choline cycle. Chemical structures of PC, LPC, GPC, choline, betaine, methionine and SAM are shown. For details, please see the text. SHMT1, serine hydroxymethyltransferase 1; MTHFR, methylenetetrahydrofolate reductase.

3. Choline/Methionine Metabolism

Choline, a quaternary amine having three methyl groups, is an essential dietary nutrient for normal body function due to its broad range of functions as a precursor of the neurotransmitter acetylcholine, as a structural component of membrane PC and sphingomyelin, and as a source of methyl group metabolism [17]. Since the amount of choline generated endogenously is thought to be insufficient to meet its demand, it needs to be obtained from food. The majority of cellular choline exists as PC in cellular membranes, indicating that this phospholipid represents the most abundant reserve pool of total cellular choline. PC can be produced from choline through de novo synthesis called the CDP-choline pathway or Kennedy pathway, in which choline is sequentially converted to phosphocholine by choline kinase (CHKA or CHKB), to CDP-choline by phosphocholine cytidylyltransferase (PCYT1), and then to PC by choline phosphotransferase (CPT1). Liver has an alternative PC-biosynthetic route that involves three-step methylation of phosphatidylethanolamine (PE) to generate PC by PE N-methyltransferase (PEMT), which accounts for 5–40% of total hepatic PC synthesis and is the only known route for de novo biosynthesis of the choline moiety in mammals [18]. PC is hydrolyzed by PLA1 or PLA2 to LPC, which is converted back to PC by lysophospholipid acyltransferases, a pathway known as the Lands’ cycle [19][20]. Additionally, LPC is further hydrolyzed by lysophospholipase to give rise to GPC, which is further split into choline and glycerol-3-phosphate (G3P) by glycerophosphodiester phosphodiesterase (GDE). The choline generated thus far is utilized for the regeneration of PC, constituting the choline cycle. In addition, methyl groups of choline are utilized for the biosynthesis of methionine specifically in hepatocytes.
Methionine is an essential and sulfur-containing amino acid that participates in various biological events, such as methylation of DNA and histones for epigenetic regulation of gene expression, redox maintenance, polyamine generation, and protein synthesis, and is also coupled with one-carbon metabolism through the folate cycle [21]. In the methionine cycle, homocysteine (Hcy) is metabolized to methionine by either methionine synthase (MTR), which transfers a methyl group from 5-methyl tetrahydrofolate (THF) in the folate cycle in concert with vitamin B12, or betaine homocysteine S-methyltransferase (BHMT), which transfers a methyl group from betaine [22][23]. Methionine is adenylated to give rise to S-adenosylmethionine (SAM) by methionine adenosyltransferase 1A (MAT1A) [29][24]. SAM is  required for transmethylation reactions for nucleic acids, proteins, lipids, and small molecules [30,31] [25][26]. SAM is converted to S-adenosylhomocysteine (SAH), a byproduct of transmethylation reactions. SAH is hydrolyzed by SAH hydrolase (AHCY) to adenosine and Hcy, the latter of which is then converted back to methionine by receiving a methyl group from 5-methyl-THF/vitamin B12 via the folate cycle or from betaine via the choline cycle [32][27]. Cellular levels of SAM vary depending on cellular nutrient conditions and affect the activity of histone methyltransferases (HMTs) and DNA methyltransferases (DNMTs) [33,34][28][29]. Histone methylation by HMTs is crucial for the regulation of chromatin remodeling and gene transcription. Methylation of the CpG islands in gene promoters by DNMTs is an important component for the epigenetic code, and many genes become abnormally methylated during tumorigenesis [35,36][30][31].  The methionine cycle is also linked to other metabolic pathways such as polyamine synthesis and transsulfuration [33,37][28][32]. Furthermore, the methyl group of SAM is transferred by PEMT to PE, resulting in the generation of PC.

4. Phenotypes of Pnpla7-Deficient Mice

Pnpla7−/− mice are born normally, yet they suffer from growth retardation after weaning and die within a few months [10]. Pnpla7−/− mice exhibit kyphosis (excessive convex backward curvature of the spine) with muscle weakness and have markedly reduced visceral and subcutaneous fats, in which adipocytes contain smaller lipid droplets and more mitochondria and show some features of beige adipocytes with greater expression of thermogenic markers such as UCP1. In addition, Pnpla7−/− mice display increases in food intake, locomotion, oxygen consumption, and dependence on lipid over carbohydrate as an energy source. The serum levels of glucose, TG, insulin and leptin are decreased, while the level of the ketone body β-hydroxybutyrate, a marker of starvation, is elevated, in Pnpla7−/− mice. Although insulin sensitivity is unaltered, hepatic gluconeogenesis and VLDL secretion are compromised by PNPLA7 deficiency. Probably due to the lower levels of blood glucose and TG as fuels, Pnpla7−/− mice have a lower body temperature. Hepatic expression of genes related to lipogenesis is decreased, while that of genes related to lipolysis and fatty acid β-oxidation is elevated, in Pnpla7–/– mice. Furthermore, PNPLA7 deficiency markedly increases the blood level of the hepatokine FGF21, which could explain some of the metabolic phenotypes observed in Pnpla7−/− mice. Metabolome analysis has revealed that the levels of GPC, choline and phosphocholine are markedly reduced, while those of LPC species are reciprocally elevated, in the liver of Pnpla7−/− mice relative to Pnpla7+/+ mice, indicating that PNPLA7 acts as a major lysophospholipase that hydrolyzes LPC to GPC in this tissue [10]. In corroboration, acute knockdown of PNPLA7 in cultured hepatocytes decreases, whereas its overexpression conversely increases, cellular GPC levels. In contrast, PNPLA7 deficiency does not profoundly affect GPC levels in non-hepatic tissues such as adipose tissue, brain and kidney, where PNPLA6 may play a major or redundant role in GPC production. Notably, hepatic levels of a series of metabolites related to the methionine cycle such as betaine, methionine, and SAM, as well as the ratio of SAM/SAH (an indicator of the methylation flux), are markedly reduced in Pnpla7−/− mice. These results suggest that PNPLA7 deficiency reduces the flux of labile methyl groups from choline driven by the PC-catabolic pathway to the methionine cycle, in association with marked changes in the levels of related metabolites in the liver, thus underscoring a crucial role of PNPLA7 in the mobilization of hydrophilic choline from hydrophobic PC. 

5. PNPLA8 Lies Upstream of PNPLA7

Of the knockout mouse strains for various PLA2s examined so far [1], only Pnpla8−/− mice share several common features with Pnpla7−/− mice. These phenotypes include reduced body weight and adiposity, muscle weakness leading to kyphosis, increased oxygen consumption, hypothermia, and reduced blood levels of glucose, TG, insulin, and leptin [2433][2534]. Among the PLA2 family, PNPLA8 shows the highest expression in mouse liver, with the magnitude order of PNPLA8 > PNPLA9 = PNPLA7 > PNPLA6 >> other PLA2s. Importantly, as in Pnpla7−/− mice, hepatic levels of GPC, choline, betaine, and SAM are substantially reduced in Pnpla8−/− mice [10]. Moreover, more than one third of the upregulated or downregulated genes, including those related to choline/methionine metabolism, fat synthesis and utilization, and glucose metabolism, in Pnpla8−/− liver are commonly changed in Pnpla7−/− liver. Hepatic expression of FGF21 is increased in both Pnpla7−/− and Pnpla8−/− mice. Thus, the phenotypes observed in Pnpla8−/− mice are strikingly similar to those observed in Pnpla7−/− mice, implying that PNPLA7 and PNPLA8 lie in the common metabolic pathway. Considering that PNPLA8 displays PLA1/PLA2 rather than lysophospholipase activity [2635], it is likely that PNPLA8 is a major upstream PLA1/PLA2 involved in the conversion of PC to LPC in the context of hepatic PC catabolism.

6. Regulation of PNPLA7 Expression in Hepatocytes by Methionine Availability

Pnpla7 expression is upregulated in the liver and adipose tissue of mice after fasting [9][10]. Since PNPLA7 is functionally linked to choline/methionine metabolism, it is likely that its expression is regulated by some metabolites in this metabolic pathway. Indeed, PNPLA7 expression is uniquely regulated by the availability of methionine and thereby SAM, being unregulated by methionine shortage and downregulated by methionine supplementation. The promoter region of the PNPLA7 gene is hypermethylated in several human hepatocellular carcinoma cell lines, including HepG2 and Huh7, and treatment of the cells with a DNMT inhibitor increases PNPLA7 expression [2736]. Hepatocytes in methionine-free culture show a lower methylation level at a CpG site in the PNPLA7 promoter than those in methionine-sufficient culture. Thus, the decreased SAM flux in methionine-deprived cells results in reduced methylation of the PNPLA7 promoter, thereby allowing increased PNPLA7 expression.

7. PNPLA7 Expression Is Decreased in Human Hepatocellular Carcinoma (HCC)

Current evidence suggests that SAM deficiency favors HCC development, which can be prevented by an exogenous supply of SAM [2837][2938]. Indeed, Mat1a-deficient mice, which display hepatic SAM deficiency, are highly susceptible to liver cancer, whereas hepatoma cells transfected with MAT1A grow more slowly than control cells [3039][3140]. In human HCC, the expression levels of PNPLA7 and PNPLA8 are markedly reduced in tumor tissues compared to non-tumor tissues, regardless of the stage or etiology of HCC. In addition to the expression levels ofPNPLA7 and PNPLA8, those of enzymes in the methionine cycle (BHMT, MAT1A, and PEMT) are also lower in the tumors than in the controls. Thus, multiple enzymes involved in PC catabolism and the methionine cycle are downregulated in HCC, implying that the reduced methyl group flux through this metabolic pathway contributes to progression of HCC.

8. Other Lysophospholipases

Beyond PNPLA7, several enzymes in the PLA2 family have been reported to possess lysophospholipase activity. As mentioned above, it is likely that PNPLA6 plays a compensatory or overlapping role with PNPLA7 in PC catabolism and recycling in tissue-specific contexts. Global Pnpla6-deficient (Pnpla6−/−) mice die in utero around E7.5 due to placental development [3241]. Brain-specific Pnpla6-deficient mice display striking defects in motor coordination and neuronal degeneration with loss of Purkinje cells, disruption of the ER, accumulation of reticular aggregates, and an increase of PC [3342], resembling the features of PNPLA6-related disorders [8] or hereditary spastic paraplegia [3443] in humans. In these mice, degeneration of the distal parts of the longest spinal axons becomes evident, with massive axon swelling in both the ascending and descending sensory and motor spinal tracts [3544], suggesting the PC/LPC catabolism driven by PNPLA6 in neurons may play a critical role in axonal membrane trafficking and secretion. All cPLA2 enzymes (group IVA-F PLA2s or cPLA2α-ζ) and PNPLA9 (group VIA PLA2 or iPLA2β) display lysophospholipase activity in vitro [3645][3746][3847][3948], yet the contribution of this activity to cPLA2- or iPLA2β-dependent biological processes remains unclear. Among the ABHD family, ABHD6 appears to function as a lysophospholipase or monoacylglycerol lipase and is involved in the regulation of endocannabinoid signaling and metabolic disease [73,74][49][50]. ABHD12 hydrolyzes lysophosphatidylserine (LysoPS) as a LysoPS-specific lysophospholipase and its genetic deletion or mutation increases LysoPS in the brain, leading to symptoms reminiscent of PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataracts) [75][51]. Lastly,  LYPLA1 and LYPLA2 are referred to as lysophospholipases, but it is now obvious that they act as acyl-thioesterases that catalyze the depalmitoylation of palmitoylated proteins [77][52].

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