Exogenous phosphatidic acid reduces acetaminophen-induced liver injury in mice by activating hepatic interleukin-6 signaling through inter-organ crosstalk

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
Pages (from-to)3836-3846
Number of pages11
JournalActa Pharmaceutica Sinica B
Volume11
Issue number12
DOIs
StatePublished - Dec 2021

Keywords

  • Acute liver failure
  • Acute liver injury
  • Adipokine
  • Cytokine
  • Dietary supplement
  • Drug-induced liver injury
  • Hepatotoxicity
  • Lipid

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