期刊
ACTA PHARMACEUTICA SINICA B
卷 11, 期 12, 页码 3836-3846出版社
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2021.08.024
关键词
Acute liver injury; Acute liver failure; Adipokine; Cytokine; Dietary supplement; Drug-induced liver injury; Hepatotoxicity; Lipid
资金
- AASLD Foundation, USA
- Arkansas Biosciences Institute, Arkansas Tobacco Settlement Proceeds Act of 2000, USA
- National Institutes of Health (USA) [T32 GM106999, R56 DK111735, R01 DK117657, R42 DK121652, R42 DK079387, UL1 TR003107, TR003108]
This study demonstrates the beneficial effects of exogenous phosphatidic acid in acetaminophen toxicity by activating IL-6 signaling. However, despite the importance of PA in liver repair, exogenous PA did not alter regeneration.
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. (C) 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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