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Review
. 2024 Apr;53(4):32.
doi: 10.3892/ijmm.2024.5356. Epub 2024 Feb 16.

Research progress, challenges and perspectives of phospholipids metabolism in the LXR‑LPCAT3 signaling pathway and its relation to NAFLD (Review)

Junmin Wang  1 , Jiacheng Li  1 , Yugang Fu  1 , Yingying Zhu  1 , Liubing Lin  1 , Yong Li  1
Affiliations
Review

Research progress, challenges and perspectives of phospholipids metabolism in the LXR‑LPCAT3 signaling pathway and its relation to NAFLD (Review)

Junmin Wang et al. Int J Mol Med. 2024 Apr.

Abstract

Phospholipids (PLs) are principle constituents of biofilms, with their fatty acyl chain composition significantly impacting the biophysical properties of membranes, thereby influencing biological processes. Recent studies have elucidated that fatty acyl chains, under the enzymatic action of lyso‑phosphatidyl‑choline acyltransferases (LPCATs), expedite incorporation into the sn‑2 site of phosphatidyl‑choline (PC), profoundly affecting pathophysiology. Accumulating evidence suggests that alterations in LPCAT activity are implicated in various diseases, including non‑alcoholic fatty liver disease (NAFLD), hepatitis C, atherosclerosis and cancer. Specifically, LPCAT3 is instrumental in maintaining systemic lipid homeostasis through its roles in hepatic lipogenesis, intestinal lipid absorption and lipoprotein secretion. The liver X receptor (LXR), pivotal in lipid homeostasis, modulates cholesterol, fatty acid (FA) and PL metabolism. LXR's capacity to modify PL composition in response to cellular sterol fluctuations is a vital mechanism for protecting biofilms against lipid stress. Concurrently, LXR activation enhances LPCAT3 expression on cell membranes and elevates polyunsaturated PL levels. This activation can ameliorate saturated free FA effects in vitro or endoplasmic reticulum stress in vivo due to lipid accumulation in hepatic cells. Pharmacological interventions targeting LXR, LPCAT and membrane PL components could offer novel therapeutic directions for NAFLD management. The present review primarily focused on recent advancements in understanding the LPCAT3 signaling pathway's role in lipid metabolism related to NAFLD, aiming to identify new treatment targets for the disease.

Keywords: ERS; LPCAT 3; LXR; NAFLD; NASH.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Hepatic phospholipid biosynthesis pathways. DAG is converted into PA by DGK. TG formation is catalyzed by DGAT. Phosphatidylethanolamine is synthesized under the action of EtnK and phospholipids are produced through the activity of ChoK and CTP: phosphocholine cytidylyltransferase (CPT). PL forms phosphatidylserine under the catalysis of PSS1, which in turn is converted into phosphatidylethanolamine by PSD. Additionally, phosphatidylethanolamine can be converted back into PL via PEMT. DAG, diacylglycerol; PA, phosphatidic acid; DGK, DAG kinase; TG, triglyceride; DGAK, DAG acyltrasferase; EtnK, ethanolamine kinase; ChoK, choline kinase; CPT, choline phosphotransferase; PL, phosphatidylcholine; PSS1, phosphatidylserine synthase 1; PSD, phosphatidylserine decarboxylase; PEMT, phosphatidylethanolamine N-methyl transferase.
Figure 2
Figure 2
Pathways of phosphatidylcholine metabolism: Kennedy pathway and Lands' cycle. In the Kennedy pathway, choline kinase catalyzes the conversion of choline into PC. PC is then converted to CDP-choline by phosphocholine cytidylyltransferase, and subsequently, CDP-choline forms PC under the action of 1,2-diacylglycerol choline-phosphotransferase. Phosphatidylethanolamine synthesizes PC through PEMT. In phospholipids, saturated and monounsaturated fatty acids typically esterify at the sn-1 position, while polyunsaturated fatty acids are esterified at the sn-2 position. The asymmetric distribution of fatty acids at sn-1 and sn-2 is established through a deacylation-reacylation process known as the Lands' cycle. The deacylation step, catalyzed by phospholipase A2, removes saturated or monounsaturated fatty acids from the sn-2 position of PCs. The reacylation step, facilitated by LPCAT, incorporates polyunsaturated fatty acids at the sn-2 position of PC. PC, phosphocholine; PEMT, phosphatidylethanolamine N-methyl transferase; LPCAT, lyso-phosphatidyl-choline acyltransferase; ATP, adenosine-triphosphate; ADP, adenosine diphosphate; CTP, cytidine triphosphate; PPi, pyrophosphoric acid; CDP, cytidine diphosphate; SAM, S-adenosyl methionine; SAH, S-Adenosyl-L-homocysteine; CoA, coenzyme A.
Figure 3
Figure 3
LPCAT3-dependent hepatic lipid metabolism pathway. In the liver, the FXR regulates cholesterol metabolism by upregulating the expression of PPAR. PPAR directly influences LPCAT3, thereby promoting the expression of SREBP-1c to regulate lipid metabolism. FXR also enhances the expression of SHP, leading to the downregulation of LXR. LXR, an upstream regulator of LPCAT3, upregulates LPCAT3 expression, which subsequently elevates SREBP-1c expression and promotes lipid metabolism. Additionally, FXR directly inhibits SREBP-1c expression, further influencing lipid metabolism. LPCAT3, lyso-phosphatidyl-choline acyltransferase 3; FXR, farnesoid X receptor; PPAR, peroxisome proliferation-activated receptor; SREBP-1c, sterol regulatory element-binding protein-1c; SHP, small heterodimer partner; LXR, liver X receptor alpha; FA, fatty acid; LDL, low density lipoprotein; TG, triglyceride; VLDL, very LDL.
Figure 4
Figure 4
Schematic diagram of apoptosis model induced by fatty acid metabolism. DAG is produced when FFA entering the glycerol backbone can be converted into LPC or TG. Steatosis or hepatitis may occur when the TG pathway or the LPC pathway, respectively, is dominant. LPC can also be derived from PA. LPC may activate the JNK pathway by activating GPCR, and may also activate the ER stress pathway, thereby inducing cell apoptosis. DAG, diacylglycerol; FFA, free fatty acid; LPC, lyso-phosphatidyl-choline; TG, triglyceride; PA, phosphatidic acid; JNK, c-Jun N-terminal kinase; GPCR, G protein-coupled receptor; ER, endoplasmic reticulum; CHOP, C/EBP homologous protein; PC, phosphatidylcholine.
Figure 5
Figure 5
LXR-LPCAT3-ERS signaling pathway. LXR affects LPCAT3 on the cell membrane, thus regulating signaling molecules associated with the ER. ER stability is maintained by three UPR pathways: PERK, ATF6 and IRE1α. Phosphorylated of PERK activates downstream EIF2α phosphorylation, regulating the expression of downstream ATF4 and CHOP expression. ATF6 directly influences XBP1 expression. IRE1α modulates the expression of downstream molecules such as ASK1, JNK and NF-κB. Under pathological conditions, aberrant activation of these pathways can alter inflammatory factor expression, leading to ER stress and cell apoptosis. LXR, liver X receptor alpha; LPCAT3, lyso-phosphatidyl-choline acyltransferase 3; ERS, ER stress; ER, endoplasmic reticulum; UP, unfolded protein; UPR, UP response; PERK, protein kinase-like ER kinase; ATF, activating transcription factor; IRE1α, inositol requiring enzyme-1α; EIF2α, eukaryotic initiation factor 2 alpha; CHOP, C/EBP homologous protein; XBP1, X-box binding protein 1; ASK1, apoptosis signal-regulating kinase 1; JNK, c-Jun N-terminal kinase; NK-κB, nuclear factor kappa B; TRAF2, TNF receptor associated factor 2.
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Grants and funding

The present study was supported by Shanghai Natural Science Foundation (grant no. 22ZR1459400) and Shanghai Science and Technology Innovation Project (grant no. 22S21901100).
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