Liquid chromatography mass spectrometry-based profiling of phosphatidylcholine and phosphatidylethanolamine in the plasma and liver of acetaminophen-induced liver injured mice
- Ya-Nan Ming†1,
- Jing-Yi Zhang†1,
- Xiao-Lin Wang2,
- Chun-Min Li1,
- Si-Cong Ma3,
- Zheng-Yang Wang4,
- Xiao-Lin Liu5,
- Xiao-Bo Li4Email author and
- Yi-Min Mao1Email authorView ORCID ID profile
© The Author(s). 2017
Received: 23 February 2017
Accepted: 2 August 2017
Published: 14 August 2017
Acetaminophen (APAP) overdose is one of the most common causes of acute liver failure in many countries. The aim of the study was to describe the profiling of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) in the plasma and liver of Acetaminophen -induced liver injured mice.
A time course study was carried out using C57BL/6 mice after intraperitoneal administration of 300 mg/kg Acetaminophen 1 h, 3 h, 6 h, 12 h and 24 h. A high-throughput liquid chromatography mass spectrometry (LC-MS) lipidomic method was utilized to detect phosphatidylcholine and phosphatidylethanolamine species in the plasma and liver. The expressions of phosphatidylcholine and phosphatidylethanolamine metabolism related genes in liver were detected by quantitative Reverse transcription polymerase chain reaction (qRT-PCR) and Western-blot.
Following Acetaminophen treatment, the content of many PC and PE species in plasma increased from 1 h time point, peaked at 3 h or 6 h, and tended to return to baseline at 24 h time point. The relative contents of almost all PC species in liver decreased from 1 h, appeared to be lowest at 6 h, and then return to normality at 24 h, which might be partly explained by the suppression of phospholipases mRNA expressions and the induction of choline kinase (Chka) expression. Inconsistent with PC profile, the relative contents of many PE species in liver increased upon Acetaminophen treatment, which might be caused by the down-regulation of phosphatidylethanolamine N-methyltransferase (Pemt).
Acetaminophen overdose induced dramatic change of many PC and PE species in plasma and liver, which might be caused by damaging hepatocytes and interfering the phospholipid metabolism in Acetaminophen -injured liver.
As a major site for drug metabolism and elimination, the liver is susceptible to drug toxicity. Drug-induced liver injury (DILI) is a significant clinical problem and a challenge for drug development worldwide. Acetaminophen (N-acetyl-p-aminophenol, APAP) is commonly used as an over-the-counter analgesic and antipyretic drug known to be safe at therapeutic doses. However, APAP overdose has become one of the most common causes of acute liver failure in many countries . APAP-induced liver injury is the most frequent drug hepatotoxicity and the most used experimental model of DILI. The mechanism of APAP-induced liver injury is complicated and not fully understood. The accumulation of N-acetyl-p-benzoquinone imine (NAPQI), the reactive and toxic metabolite of APAP, is considered as the main cause of liver injury induced by overdose of APAP. In mouse APAP-induced models and in human, the reaction of NAPQI with protein sulfhydryl groups of cysteine might trigger mitochondrial damage, oxidative stress, c-jun N-terminal kinase (JNK) activation, the nuclear DNA fragmentation and cell death [2–4].
In mammalian cells, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are the first and second most abundant phospholipid respectively. In liver, PC is the principal component of cellular membrane, a precursor of signaling molecules, and a key element of lipoproteins and bile. In addition to its structural role in membrane and as a substrate for methylation to PC in the liver, PE is also a substrate for anandamide synthesis, regulates membrane fusion, and supplies ethanolamine for glycosylphosphatidylinositol anchors of cell-surface signaling proteins. Previous studies over 50 years ago reported the contents of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were decreased,but the PE:PC ratio was elevated in the liver of rats challenged with CCl4 [5, 6]. Lipidomics is a powerful technology defined as the complete quantitative and molecular determination of lipid molecules isolated from cells, tissue or biological fluid [7–9]. During APAP-induced liver injury, lipidome is the overall results of cellular/subcellular dysfunction and alterations of larges molecules like proteins/enzymes/DNA, and consequently more easily correlated with the phenotype. The analysis of lipidome by lipidomics direct to a more detailed understanding of biochemical changes during DILI.
Recent years, emerging lipidomic techniques were used to describe comprehensive and global PC/PE profiles in plasma/liver of experimental animals with drug/chemical-induced liver injury. Several studies reported that serum levels of certain PCs/PEs were significantly changed in acute rat liver injury induced by chemicals such as APAP, CCL4, galactosamine and ricinine [10–12]. Cheng J et al. analyzed APAP-treated mice serum through LC-MS-based metabolomics, and they found that C20:4-LPC gradually declined with rising liver toxicity . Xie T et al. observed the remodeling of PC/PE in liver of rats with Tripterygium wilfordii induced liver injury. The alternations comprised fatty acid composition of PC changed and increased Lyso PC and certain PE decreased, which might affect membrane fluidity, the inflammatory reaction, and mitochondria dysfunction respectively . However, the alternation of individual PC/PE specie in both plasma and liver of APAP-injured mice and correlations of PCs/PEs between plasma and liver remains unknown. We already developed an LC-MS based lipidomic method for simultaneous detection of diverse lipids . In the present study, using this high-throughput method, we compared the relative concentrations of phosphatidylcholine and phosphatidylethanolamine in the plasma and liver of the APAP-induced liver injured mice and saline-treated control mice at series of time-points, and then measured the expressions of genes involved in PC/PE metabolism in liver. The experimental work is focusing on the search for possible mechanisms leading to hepatotoxicity than on biomarkers indicating an APAP intoxication.
Biochemical assays and H&E staining
Phosphatidylcholine and phosphatidylethanolamine profiling in mice plasma analyzed by LC-MS
The ratio of lipid concentrations in APAP-treated group/lipid concentrations in saline-treated group at each time-point was calculated and represented as the relative concentrations of APAP-treated group in Additional file 1: Table S1. The fold-changes of PC/PE species in mouse plasma upon APAP treatment were also illustrated by heat map in Supplemental Additional file 2: Figure S1A (PC) and Figure S1B (PE).
The profiles of PC and PE in mice livers analyzed by LC-MS
The expression pattern of PC and PE metabolism related genes in APAP-injured mice livers
In the present study, we utilized the high-throughput LC-MS lipidomic method to acquire PC and PE profiles both in plasma and liver of APAP-induced liver injured mice at different time points after dosing.
The mice model of APAP-induced liver injury mostly resembles the human pathophysiology of both liver injury and recovery . In our study, the sub-lethal dose of APAP (300 mg/kg) was used to induce liver injury in mice. In this model, the most significant increase of ALT/AST is at 6 h time point. At 24 h time point, the liver function presented the recovery situation verified by enzymatic and morphological evaluation. Consistently, the most dramatic change of PC/PE profiles occurred at 3 h and 6 h time points, so varied PC/PE at both 3 h and 6 h time points were emphasized in our analysis.
As lipids serve many important functions, take part in several biochemical reactions and integrate diverse metabolic pathways, any alteration in lipids will reflect and affect cellular functions. Based on our results, the content of many PC/PE species in plasma increased from 1 h time point, peaked at 3 h or 6 h, and tended to return normality at 24 h time point. PC 33:1, PC 34:3, PE 34:2, PE 36:3, PE 38:4 and PE 38:6 were elevated significantly both at 3 h and 6 h time points upon APAP treatment. The increases of these 6 phospholipids were positively correlated with the changes of ALT/AST. The alternation of PC/PE lipidome in plasma might be caused by damaging hepatocytes and/or interfering the lipid metabolism in liver. Based on our results, following an intoxication with APAP, many PC/PE species such as PC 33:1, PC 34:3, PE 34:2 and PE 36:3 in liver tissue decreased from 1 h, appeared to be lowest at 6 h, and had the tendency back to normal status at 24 h time point, which was opposite to their profile in plasma. Therefore, the increase of these phospholipids in plasma might be released by damaged hepatocytes in APAP-injured livers. However, some PEs increased in APAP-injured livers, which might cause the induction of certain PEs such as PE 38:4 and PE 38:6 in plasma.
The contents of PC/PE in liver rely on their degradation and synthesis. The degradation of PC/PE results from the action of phospholipases. There are various phospholipases (PLA1, PLA2, PLC and PLD) that exhibit substrate specificities for different positions in phospholipids. Phospholipase A2 (PLA2) hydrolyzes the sn-2 ester bond in PC/PE, forming arachidonic acid and lyso-PC/lyso-PE [17–19]. These bioactive lipid mediators play important roles in inflammation, phospholipid metabolism, and signal transduction, which participate in the progression of DILI. The PLA2 superfamily includes over twenty groups comprising such main types as the secreted sPLA2, cytosolic cPLA2, calcium-independent iPLA2, and so on. PC and PE also could be degraded by PLA1, PLC and PLD . The decrease of PC contents might be the consequence of increased activities of phospholipases. Previous studies demonstrate that overdose of APAP may activate cPLA2 and sPLA2 [21–23], which are involved in APAP toxicity. The activated phospholipases degraded PC in livers. Our present study indicated that the mRNA levels of phospholipases were suppressed by APAP treatment, which might be the adaptive protective reaction for the remaining alive hepatocytes.
Except for degradation, the contents of phospholipids in liver are also affected by their synthesis. The major pathway of PC synthesis is the CDP-choline pathway, also referred to as the “Kennedy pathway”, which requires choline and three enzymes including choline kinase (Chka and Chkb), CTP:phosphocholine cytidylyltransferase (Pcyt) and diacylglycerol cholinephosphotransferase (Chpt). In liver, PC can also be generated endogenously in a second pathway via PE methylations catalyzed by hepatic phosphatidylethanolamine N-methyltransferase (PEMT), which produces about one third of the PC in liver. PC also could be synthesized by reacylation of lyso-PC with lyso-PC acyltransferase (LPCAT) [24, 25]. We observed that the mRNA and protein levels of Chka, the rate-limiting enzyme of synthesizing PC de novo, were induced dramatically in APAP-injured mice. Chka was found to play a vital role in many biological signaling pathway, such as androgen receptor (AR) chaperone , and cell proliferation and carcinogenesis. Extensive studies of the structure and function of Chka show that the distal of the Chka promoter regions sequence is similar to the consensus of activated protein-1 binding site .In addition, APAP overdose causes nuclear accumulation of Hypoxia inducible factor-1 (HIF-1) in mouse livers as early as 1 h after treatment . The expression of Chka was identified to be due to the regulation of transcriptional expression of HIF-1 . HIF-1 deficiency mice were protected from APAP hepatotoxicity at 6 h, but severe liver injury was observed at 24 h, suggesting that HIF-1 is involved in the early stage of APAP toxicity . Thus, the altered characteristic of Chka may be related to the alteration of associated transcriptional factors. The increased activities of phospholipases, decreased phospholipases mRNA expressions, and increased Chka mRNA/protein expression might partly explain why the contents of PC species in livers increased after APAP dosing and tended to recover at 24 h time point. PE is synthesized by four different pathways, the two quantitatively major of which are the CDP-ethanolamine pathway that PE catalyzed by ethanolamine kinase (ETNK1 and ETNK2) in the ER and the PS decarboxylation pathway that catalyzed by phosphatidylserine decarboxylase (PISD) in mitochondria . The increase of some PE species in APAP-injured livers might be involved in the suppression of Pemt which is responsible one third of PC synthesis in liver. The dramatic decrease of Pemt may lead the accumulation of PE in APAP-injured liver.
Our study for the first time determined the dynamic PC/PE changes both in plasma and liver that occurred in APAP-induced liver injury by lipidomics. This time-course study provides a deeper understanding of the metabolic changes observed in APAP-induced liver injury. We took the plasma PC/PE lipidome, liver tissue PC/PE lipidome, and PC/PE metabolism-related gene expressions into consideration intergratedly. The comprehensive analysis might contribute to a better understanding the effect of APAP on lipid metabolism, hence finding potential therapeutic targets. In future studies, the concentration dependent changes of the PC/PE species in mice upon APAP treatment should be observed, which might provide valuable information for judging prognosis of DILI. Huo T et al. performed both UPLC-MS and (1)HNMR-based metabonomics analysis of serum samples from 34 epileptic patients after valproate sodium treatment, and found that certain LPCs such as LPC 16:0, LPC 18:0, LPC 18:1 and LPC 18:2 decreased in valproate sodium induced liver injury . The phospholipid profile of serum in human intoxicated with APAP also might be further observed by lipidomic techniques.
These results suggest that a novel targeted lipidomic method based on the metabolic profiling of phospholipid analyzed by LC-MS provides a better understanding the role of lipid metabolism in APAP-induced injured liver and serum, which might provide valuable information for judging prognosis of DILI and therapeutic targets.
C57BL/6 males aged 8–10 weeks and weighed 22–25 g at the time of the experimental procedures were purchased from the Shanghai Laboratory Animal Center, Chinese Academy Sciences (Shanghai, China). All mice were housed in microisolator cages under humidity- (50% ± 5%) and temperature- (24° ± 2 °C) controlled specific pathogen-free conditions with 12 h light/dark cycle. The mice were maintained on with free access to water and standard irradiated sterile chow.
Treatment of mice
Fresh acetaminophen (Sigma Aldrich, USA) solution was prepared for each experiment by dissolving acetaminophen in saline warmed to 59 °C. Mice were fasted for 16 h and then injected intraperitoneally (i.p.) with saline or acetaminophen at 300 mg/kg (body weight) and food restored. APAP-treated mice were sacrificed and collected liver and plasma samples at the indicated time points (0 h, 1 h, 3 h, 6 h, 12 h, and 24 h, n = 6 ~ 8 each time point). Some mice were treated with saline as parallel controls at the same time points (1 h, 3 h, 6 h, 12 h, and 24 h, n = 6 ~ 8 each time point). Appropriate volume of PMSF stock solution in isopropanol (100 mM) were added to freshly collected mouse plasma (5 mM in plasma) to stabilize the plasma lipidome. The livers were frozen in −80 °C for later lipid/total RNA/protein extraction or fixed in 4% paraformaldehyde for tissue sections.
The lipids of plasma (50 uL) and liver samples (200 mg) were extracted using liquid-liquid methyl tert-butyl ether (MTBE) extraction protocols developed by our group . Briefly, endogenous free lipids including PE (17:0/17:0), PC (19:0/19:0), LPE 14:0, LPC 17:0 were selected as the internal standard for their corresponding lipid classes. The lipids of the mixture of the above mixed internal standard solution and samples were extracted twice using MTBE, dried and finally reconstituted in 200 μL in the mixture of isopropanol/acetonitrile/water (75:20:5, v/v/v), then subjected to LC-MS analysis. An HPLC-quadrupole-time of flight hybrid mass system, which consisted of a LC-30 AD UFLC system (Shimadzu, Kyoto, Japan) and a TripleTOF 5600þ quadrupole time of flight mass spectrometer (AB SCIEX, MA, USA), was used for lipidomic analysis. Chromatography was performed on a charged surface hybrid (CSH™) C18, 2.1*100 mm, 1.7 um UPLC column (Waters Corporation, USA) and subjected to a gradient elution as described previously. The eluents were monitored in positive electronic ion spray ESI mode. The lipid profiling was performed using the previous methods . Briefly, the extracted ions chromatogram (EIC) of each lipid specie was created by applying the molecular weight (MW) lists (MW of quasi-molecular ions) generated from Lipidview™ software (AB SCIEX, MA, USA). The peaks found in EIC were screened and identified according to the rules, including exact mass accuracy (< 5 ppm), specific fragment (PC and LPC have the specific product of 184.1; PE and LPE have the specific neutral loss of 141), retention time and isotope distribution pattern (similarity to the theoretical pattern). After corresponding IS correction, the areas of the identified peaks were used for quantitation.
Biochemical assays and histopathology
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by an automatic biochemical analyzer (SIEMENS ADVIA 1800: SIEMENS Healthcare Diagnostics, USA). Liver sections from saline- or APAP-treated mice were fixed in 4% paraformaldehyde overnight and embedded in paraffin wax, sliced at 5 mm thickness and stained with hematoxylin and eosin (H&E).
Real-time RT-PCR (qRT-PCR) analysis
Primers sets used for qPCR
Genbank accession NM
Western blot analysis
Total protein was extracted from treated livers using radioimmune precipitation assay (RIPA) lysis buffer. The Chka protein level was detected by primary antibody against Chka (Proteintech Group, Inc. Rosemont, IL, USA) using Western blot assay according to published methods . β-actin was used as loading control.
MultiQuant™ software (Version 2.1.1, AB SCIEX, MA, USA), calculated the peak area ratios of lipid species and their corresponding internal standards, as the concentrations of lipid species. PCA and PLS-DA were performed using SIMCA-P 12.0 software (Umetrics, Umea, Sweden). The original data of PC/PE concentrations and the fold changes of APAP-treated mice compared with saline-treated mice at indicated time points in plasma and liver were shown in Supplemental tables (Additional file 1: Table S1 and Additional file 4: Table S2) respectively. The original data were presented as the mean ± SD. To compare the concentrations of PC/PE between the APAP-treated group and saline-treated group in each indicated time point, statistical analysis was performed with t-tests for unpaired data, the statistical significance was corrected for multiple comparisons using the Holm-sidak method by using GraphPad Prism 6.0.
This work was supported by the Major Project of National Twelfth Five Plan (2012ZX09303–001 and 2013ZX10002004), National Natural Science Foundation of China (NSFC 81270497).
Availability of data and materials
YM M and XB L designed and wrote the paper. YN M performed the majority of research. All authors have read and approved the final manuscript.
Ethics approval and consent to participate
All experiments were performed with the approval of Shanghai Jiaotong University School of medicine animal ethics committee.
Consent for publication
The authors declare that they have no competing interests.
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