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
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
Author description:
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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

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