Growth Hormone Accelerates Recovery From Acetaminophen-Induced Murine Liver Injury

Everton, E.; del Rio Moreno, M.; Villacorta-Martin, C.; Singh Bawa, P.; Lindstrom-Vautrin, J.; Muramatsu, H.; Rizvi, F.; Smith, A. R.; Tam, Y.; Pardi, N.; Kineman, R.; Waxman, D. J.; Gouon-Evans, V.

doi:10.1101/2023.04.17.537197

bioRxiv · 10.1101/2023.04.17.537197

Growth Hormone Accelerates Recovery From Acetaminophen-Induced Murine Liver Injury

Everton, E.·del Rio Moreno, M.·Villacorta-Martin, C.·Singh Bawa, P.·Lindstrom-Vautrin, J.·Muramatsu, H.·Rizvi, F.·Smith, A. R.·Tam, Y.·Pardi, N.·Kineman, R.·Waxman, D. J.·Gouon-Evans, V.

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Abstract

Background and AimsAcetaminophen (APAP) overdose is the leading cause of acute liver failure, with one available treatment, N-acetyl cysteine (NAC). Yet, NAC effectiveness diminishes about ten hours after APAP overdose, urging for therapeutic alternatives. This study addresses this need by deciphering a mechanism of sexual dimorphism in APAP-induced liver injury, and leveraging it to accelerate liver recovery via growth hormone (GH) treatment. GH secretory patterns, pulsatile in males and near-continuous in females, determine the sex bias in many liver metabolic functions. Here, we aim to establish GH as a novel therapy to treat APAP hepatotoxicity. Approach and ResultsOur results demonstrate sex-dependent APAP toxicity, with females showing reduced liver cell death and faster recovery than males. Single-cell RNA sequencing analyses reveal that female hepatocytes have significantly greater levels of GH receptor expression and GH pathway activation compared to males. In harnessing this female-specific advantage, we demonstrate that a single injection of recombinant human GH protein accelerates liver recovery, promotes survival in males following sub-lethal dose of APAP, and is superior to standard-of-care NAC. Alternatively, slow-release delivery of human GH via the safe nonintegrative lipid nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP), a technology validated by widely used COVID-19 vaccines, rescues males from APAP-induced death that otherwise occurred in control mRNA-LNP-treated mice. ConclusionsOur study demonstrates a sexually dimorphic liver repair advantage in females following APAP overdose, leveraged by establishing GH as an alternative treatment, delivered either as recombinant protein or mRNA-LNP, to potentially prevent liver failure and liver transplant in APAP-overdosed patients.

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Everton, E., del Rio Moreno, M., Villacorta-Martin, C., Singh Bawa, P., Lindstrom-Vautrin, J., Muramatsu, H., Rizvi, F., Smith, A. R., Tam, Y., Pardi, N., Kineman, R., Waxman, D. J., Gouon-Evans, V.. 2023-04-18. Growth Hormone Accelerates Recovery From Acetaminophen-Induced Murine Liver Injury. https://doi.org/10.1101/2023.04.17.537197

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