Original articles
Melissa M. Clemens, Stefanie Kennon-McGill, Joel H. Vazquez, Owen W. Stephens, Erich A. Peterson, Donald J. Johann, Felicia D. Allard, Eric U. Yee, Sandra S. McCullough, Laura P. James, Brian N. Finck, Mitchell R. McGill. Exogenous phosphatidic acid reduces acetaminophen-induced liver injury in mice by activating hepatic interleukin-6 signaling through inter-organ crosstalk[J]. Acta Pharmaceutica Sinica B, 2021, 11(12): 3836-3846

Exogenous phosphatidic acid reduces acetaminophen-induced liver injury in mice by activating hepatic interleukin-6 signaling through inter-organ crosstalk
Melissa M. Clemensa,b, Stefanie Kennon-McGillc, Joel H. Vazqueza,b, Owen W. Stephensd, Erich A. Petersond, Donald J. Johannd, Felicia D. Allarde, Eric U. Yeee, Sandra S. McCulloughf, Laura P. Jamesf, Brian N. Finckg, Mitchell R. McGilla,c,h
a. Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
b. Interdisciplinary Graduate Program in Biomedical Sciences, Graduate School, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
c. Department of Environmental and Occupational Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
d. Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
e. Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA;
f. Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
g. Division of Geriatrics and Nutritional Sciences, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA;
h. Center for Dietary Supplement Research, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Abstract:
We previously demonstrated that endogenous phosphatidic acid (PA) promotes liver regeneration after acetaminophen (APAP) hepatotoxicity. Here, we hypothesized that exogenous PA is also beneficial. To test that, we treated mice with a toxic APAP dose at 0 h, followed by PA or vehicle (Veh) post-treatment. We then collected blood and liver at 6, 24, and 52 h. Post-treatment with PA 2 h after APAP protected against liver injury at 6 h, and the combination of PA and N-acetyl-l-cysteine (NAC) reduced injury more than NAC alone. Interestingly, PA did not affect canonical mechanisms of APAP toxicity. Instead, transcriptomics revealed that PA activated interleukin-6 (IL-6) signaling in the liver. Consistent with that, serum IL-6 and hepatic signal transducer and activator of transcription 3 (Stat3) phosphorylation increased in PA-treated mice. Furthermore, PA failed to protect against APAP in IL-6-deficient animals. Interestingly, IL-6 expression increased 18-fold in adipose tissue after PA, indicating that adipose is a source of PA-induced circulating IL-6. Surprisingly, however, exogenous PA did not alter regeneration, despite the importance of endogenous PA in liver repair, possibly due to its short half-life. These data demonstrate that exogenous PA is also beneficial in APAP toxicity and reinforce the protective effects of IL-6 in this model.
Key words:    Acute liver injury    Acute liver failure    Adipokine    Cytokine    Dietary supplement    Drug-induced liver injury    Hepatotoxicity    Lipid   
Received: 2021-03-11     Revised: 2021-07-26
DOI: 10.1016/j.apsb.2021.08.024
Funds: This study was funded in part by a 2018 Pinnacle Research Award from the AASLD Foundation, USA (Mitchell R. McGill); the Arkansas Biosciences Institute (Mitchell R. Mc Gill), which is the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000, USA; and the National Institutes of Health grants (USA) T32 GM106999 (Mitchell R. McGill and Joel H. Vazquez), R01 DK104735 (Brian N. Finck), R01 DK117657 (Brian N. Finck), R42 DK121652 (Brian N. Finck), R56 DK111735 (Brian N. Finck), R42 DK079387 (Laura P. James), UL1 TR003107 (Laura P. James and Stefanie Kennon-McGill), and TR003108 (Laura P. James and Stefanie Kennon-McGill). We are grateful for expert technical assistance provided by the Dept. of Laboratory Animal Medicine at UAMS, USA (especially Robin Mulkey) and by the Experimental Pathology Core, USA [especially Jennifer D. James, HT (ASCP), HTL, QIHC].
Corresponding author: Mitchell R. McGill,E-mail:mmcgill@uams.edu     Email:mmcgill@uams.edu
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Authors
Melissa M. Clemens
Stefanie Kennon-McGill
Joel H. Vazquez
Owen W. Stephens
Erich A. Peterson
Donald J. Johann
Felicia D. Allard
Eric U. Yee
Sandra S. McCullough
Laura P. James
Brian N. Finck
Mitchell R. McGill

References:
[1] Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002;287:337-344
[2] Lee WM. Etiologies of acute liver failure. Semin Liver Dis 2008;28:142-152
[3] Jollow DJ, Mitchell JR, Potter WZ, Davis DC, Gillette JR, Brodie BB. Acetaminophen induced hepatic necrosis. II. Role of covalent binding in vivo. J Pharmacol Exp Ther 1973;187:195-202
[4] Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB. Acetaminophen induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther 1973;187:211-217
[5] McGill MR, Hinson JA. The development and hepatotoxicity of acetaminophen: reviewing over a century of progress. Drug Metab Rev 2020;52:472-500
[6] Jaeschke H. Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo: the protective effect of allopurinol. J Pharmacol Exp Ther 1990;255:935-941
[7] Cover C, Mansouri A, Knight TR, Bajt ML, Lemasters JJ, Pessayre D, et al. Peroxynitrite-induced mitochondrial and endonuclease-mediated nuclear DNA damage in acetaminophen hepatotoxicity. J Pharmacol Exp Ther 2005;315:879-887
[8] Gunawan BK, Liu ZX, Han D, Hanawa N, Gaarde WA, Kaplowitz N. c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity. Gastroenterology 2006;131:165-178
[9] Hanawa N, Shinohara M, Saberi B, Gaarde WA, Han D, Kaplowitz N. Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. J Biol Chem 2008;283:13565-13577
[10] Ramachandran A, McGill MR, Xie Y, Ni HM, Ding WX, Jaeschke H. Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice. Hepatology 2013;58:2099-2108
[11] Win S, Than TA, Min RWM, Aghajan M, Kaplowitz N. c-Jun N-terminal kinase mediates mouse liver injury through a novel Sab (SH3BP5)-dependent pathway leading to inactivation of intramitochondrial Src. Hepatology 2016;63:1987-2003
[12] Kon K, Kim JS, Jaeschke H, Lemasters JJ. Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes. Hepatology 2004;40:1170-1179
[13] Reid AB, Kurten RC, McCullough SS, Brock RW, Hinson JA. Mechanisms of acetaminophen-induced hepatotoxicity: role of oxidative stress and mitochondrial permeability transition in freshly isolated mouse hepatocytes. J Pharmacol Exp Ther 2005;312:509-516
[14] Bajt ML, Cover C, Lemasters JJ, Jaeschke H. Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury. Toxicol Sci 2006;94:217-225
[15] Gujral JS, Knight TR, Farhood A, Bajt ML, Jaeschke H. Mode of cell death after acetaminophen overdose in mice: apoptosis or oncotic necrosis?. Toxicol Sci 2002;67:322-328
[16] McGill MR, Yan HM, Ramachandran A, Murray GJ, Rollins DE, Jaeschke H. HepaRG cells: a human model to study mechanisms of acetaminophen hepatotoxicity. Hepatology 2011;53:974-982
[17] McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest 2012;122:1574-1583
[18] Kooijman EE, Chupin V, de Kruijff B, Burger KNJ. Modulation of membrane curvature by phosphatidic acid and lysophosphatidic acid. Traffic 2003;4:162-174
[19] Pokotylo I, Kravets V, Martinec J, Ruelland E. The phosphatidic acid paradox: too many actions for one molecule class? Lessons from plants. Prog Lipid Res 2018;71:43-53
[20] Fang Y, Vilella-Bach M, Flanigan A, Chen J. Phosphatidic acid-mediated activation of mitogenic mTOR signaling. Science 2001;294:1942-5
[21] Foster DA. Phosphatidic acid and lipid-sensing by mTOR. Trends Endocrinol Metab 2013;24:272-278
[22] Lutkewitte AJ, Schweitzer GG, Kennon-McGill S, Clemens MM, James LP, Jaeschke H, et al. Lipin deactivation after acetaminophen overdose causes phosphatidic acid accumulation in liver and plasma in mice and humans and enhances liver regeneration. Food Chem Toxicol 2018;115:273-283
[23] Clemens MM, Kennon-McGill S, Apte U, James LP, Finck BN, McGill MR. The inhibitor of glycerol 3-phosphate acyltransferase FSG67 blunts liver regeneration after acetaminophen overdose by altering GSK3β and Wnt/β-catenin signaling. Food Chem Toxicol 2019;125:279-288
[24] Du K, Williams CD, McGill MR, Jaeschke H. Lower susceptibility of female mice to acetaminophen hepatotoxicity: role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase. Toxicol Appl Pharmacol 2014;281:58-66
[25] Rubin JB, Hameed B, Gottfried M, Lee WM, Sarkar M. Acetaminophen-induced acute liver failure is more common and more severe in women. Clin Gastroenterol Hepatol 2018;16:936-946
[26] McGill MR, Jaeschke H. A direct comparison of methods used to measure oxidized glutathione in biological samples: 2-vinylpyridine and N-ethylmaleimide. Toxicol Mech Methods 2015;25:589-595
[27] Muldrew KL, James LP, Coop L, McCullough SS, Hendric kson HP, Hinson JA, et al. Determination of acetaminophen-protein adducts in mouse liver and serum and human serum after hepatotoxlc doses of acetaminophen using high-performance liquid chromatography with electrochemical detection. Drug Metab Dispos 2002;30:446-451
[28] McGill MR, Lebofsky M, Norris HRK, Slawson MH, Bajt ML, Xie Y, et al. Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: dose-response, mechanisms, and clinical implications. Toxicol Appl Pharmacol 2013;269:240-249
[29] Shinohara M, Ybanez MD, Win S, Than TA, Jain S, Gaarde WA, et al. Silencing glycogen synthase kinase-3β inhibits acetaminophen hepatotoxicity and attenuates JNK activation and loss of glutamate cysteine ligase and myeloid cell leukemia sequence. J Biol Chem 2010;285:8244-8255
[30] Hu J, Ramshesh VK, McGill MR, Jaeschke H, Lemasters JJ. Low dose acetaminophen induces reversible mitochondrial dysfunction associated with transient c-Jun N-terminal kinase activation in mouse liver. Toxicol Sci 2016;150:204-215
[31] Bhattacharyya S, Yan K, Pence L, Simpson PM, Gill P, Letzig LG, et al. Targeted liquid chromatography-mass spectrometry analysis of serum acylcarnitines in acetaminophen toxicity in children. Biomark Med 2014;8:147-159
[32] Borude P, Bhushan B, Gunewardena S, Akakpo J, Jaeschke H, Apte U. Pleiotropic role of p53 in injury and liver regeneration after acetaminophen overdose. Am J Pathol 2018;188:1406-1418
[33] Gao RY, Wang M, Liu Q, Feng D, Wen Y, Xia Y, et al. Hypoxia-inducible factor (HIF)-2α reprograms liver macrophages to protect against acute liver injury via the production of interleukin-6. Hepatology 2020;71:2105-2117
[34] Lim HK, Choi YA, Park W, Lee T, Ryu SH, Kim SY, et al. Phosphatidic acid regulates systemic inflammatory responses by modulating the Akt-mammalian target of rapamycin-p70 S6 kinase 1 pathway. J Biol Chem 2003;278:45117-45127
[35] Clemens MM, McGill MR, Apte U. Mechanisms and biomarkers of liver regeneration after drug-induced liver injury. Adv Pharmacol 2019;85:241-262
[36] Masubuchi Y, Bourdi M, Reilly TP, Graf ML, George JW, Pohl LR. Role of interleukin-6 in hepatic heat shock protein expression and protection against acetaminophen-induced liver disease. Biochem Biophys Res Commun 2003;304:207-212
[37] Tolson JK, Dix DJ, Voellmy RW, Roberts SM. Increased hepatotoxicity of acetaminophen in Hsp70i knockout mice. Toxicol Appl Pharmacol 2006;210:157-162
[38] Ni HM, McGill MR, Chao X, Du K, Williams JA, Xie Y, et al. Removal of acetaminophen protein adducts by autophagy protects against acetaminophen-induced liver injury in mice. J Hepatol 2016;65:354-362
[39] Cuervo AM, Wong E. Chaperone-mediated autophagy: roles in disease and aging. Cell Res 2014;24:92-104
[40] Dong J, Viswanathan S, Adami E, Schafer S, Kuthubudeen FF, Widjaja AA, et al. Overturning the paradigm that IL6 signaling drives liver regrowth while shining light on a new therapeutic target for regenerative medicine. bioRxiv 2021. Available from: https://www.biorxiv.org/content/10.1101/2021.04.05.438446v1.
[41] Bae GH, Lee SK, Kim HS, Lee M, Lee HY, Bae YS. Lysophosphatidic acid protects against acetaminophen-induced acute liver injury. Exp Mol Med 2017;49:e407
[42] Cressman DE, Greenbaum LE, DeAngelis RA, Ciliberto G, Furth EE, Poli V, et al. Liver failure and defective hepatocyte regeneration in interleukin-6- deficient mice. Science 1996;274:1379-1383
[43] Selzner M, Camargo CA, Clavien PA. Ischemia impairs liver regeneration after major tissue loss in rodents: Protective effects of interleukin-6. Hepatology 1999;30:469-475
[44] James LP, Lamps LW, McCullough S, Hinson JA. Interleukin 6 and hepatocyte regeneration in acetaminophen toxicity in the mouse. Biochem Biophys Res Commun 2003;309:857-863
[45] Rio A, Gassull MA, Aldeguer X, Ojanguren I, Cabre E, Fernandez E. Reduced liver injury in the interleukin-6 knockout mice by chronic carbon tetrachloride administration. Eur J Clin Invest 2008;38:306-316
[46] Bajt ML, Knight TR, Farhood A, Jaeschke H. Scavenging peroxynitrite with glutathione promotes regeneration and enhances survival during acetaminophen-induced liver injury in mice. J Pharmacol Exp Ther 2003;307:67-73
[47] Shad BJ, Smeuninx B, Atherton PJ, Breen L. The mechanistic and ergogenic effects of phosphatidic acid in skeletal muscle. Appl Physiol Nutr Metab 2015;40:1233-1241
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