Exogenous phosphatidic acid reduces acetaminophen-induced liver injury in mice by activating the interleukin-6-Hsp70 axis through inter-organ crosstalk

Abstract

We previously demonstrated that endogenous phosphatidic acid (PA) promotes liver regeneration after acetaminophen (APAP) hepatotoxicity in mice. Based on that, 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 at multiple timepoints. We then collected blood and liver at 6, 24, and 52 h. Post-treatment with PA protected against liver injury at 6 h, and the combination of PA and N-acetyl-cysteine (NAC) further reduced injury compared to NAC alone. Interestingly, PA had no effect on major early mechanisms of APAP toxicity, including APAP bioactivation, oxidative stress, JNK activation, and mitochondrial damage. However, transcriptomics revealed that PA activated interleukin-6 (IL-6) signaling in the liver, and IL-6 was increased in serum from PA-treated mice. Furthermore, PA did not protect against APAP in IL-6-deficient mice. In addition, IL-6 expression increased 18-fold in adipose tissue after PA, indicating that adipose tissue is a likely source of the increased IL-6 due to PA treatment. Surprisingly, however, exogenous PA did not alter regeneration, despite the widely accepted role of IL-6 in liver repair. These data reinforce the protective role of IL-6 in APAP hepatotoxicity, provide new insight into the role of IL-6 in liver regeneration, and indicate that exogenous PA or PA derivatives may one day be a useful adjunct treatment for APAP overdose with NAC.