Sexual dimorphism of acetaminophen-induced liver injury and regeneration

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ABSTRACT Acetaminophen (acetyl-para-aminophenol or APAP) is the most commonly used pain reliever in the United States, yet acetaminophen overdose is the leading cause of acute liver failure in the developed world. Currently the only available treatments are N-acetyl cysteine (NAC), which only has a short window of effectiveness, or ultimately liver transplant. Therefore, therapeutic alternatives to treat APAP overdose are urgently needed in the clinic. This proposal will address this issue by deciphering the mechanisms of sexual dimorphism of APAP-induced liver injury and repair, and to leverage this sexual dimorphism by establishing how hormone therapy will accelerate liver recovery in both sexes following APAP overdose. Sex hormones and their receptors have been implicated in driving sexual dimorphism in many liver processes. Specifically, higher average levels of growth hormone (GH) secretion in females contributes to higher metabolic activity in their livers. Consistent with the literature, our preliminary data support the higher resistance of female mice to APAP, shown by reduced liver necrosis, cell death, and detection of serum injury markers compared to males. Moreover, our single-cell RNA sequencing analyses reveal that female hepatocytes and endothelial cells (ECs) express significantly higher levels of GH receptor and GH pathway activation than male cells, while males have upregulated inflammatory and cell death pathway activation. In preparation for this application, we generated preliminary data showing that GH treatment significantly and rapidly repairs the tissues of both males and females following sub-lethal doses of APAP, as quantified by tissue necrosis, cell death, and mouse survival. These key data suggest a sexually dimorphic liver regenerative advantage in females, which can be recapitulated with GH treatment to induce recovery in males and accelerate recovery in females. Therefore, we hypothesize that there is a sexual dimorphism in APAP sensitivity that we can leverage with the use of GH to accelerate liver regeneration in both sexes. In this proposal, we will further examine the role of GH and its pathway activation in hepatocytes and ECs following APAP overdose via single-cell RNA sequencing analysis and hepatocyte and EC -specific GH receptor knockouts. We will leverage these findings to establish an optimal GH therapy with identification of GH specific doses and time frame of effectiveness for each sex to mitigate liver injury and accelerate liver regeneration with superior efficacy to the current standard-of-care NAC. Potential additive therapeutic effect of combined GH/NAC treatment will be also determined. In conclusion, understanding the biological mechanisms behind the sexual disparity in APAP-induced liver injury, subsequent regeneration, and modulation by GH will provide the biological foundation to establish a GH therapy to treat APAP overdose in both sexes, a currently unmet clinical need.