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

• 作者: 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
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（12）
• 所属期刊栏目: Original articles
• 页码范围: 3836-3846
• 页数: 11页
• 语种: 英文

摘要

We previously demonstrated that endogenous phosphatidic acid(PA)promotes liver regener-ation after acetaminophen(APAP)hepatotoxicity.Here,we hypothesized that exogenous PA is also bene-ficial.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)phosphoryla-tion increased in PA-treated mice.Furthermore,PA failed to protect against APAP in IL-6-deficient an-imals.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 regenera-tion,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 ef-fects of IL-6 in this model.