Carbon monoxide ameliorates acetaminophen‐induced liver injury by increasing hepatic HO‐1 and Parkin expression

Acetaminophen (APAP) is widely used as an antifebrile and analgesic drug at recommended doses, whereas an overdose of APAP can cause severe liver damage. The molecular mechanisms underlying APAP‐induced liver damage remain incompletely understood. Carbon monoxide (CO), an end‐product of heme oxygenase (HO)‐1 activity, can confer anti‐inflammatory and antiapoptotic properties in cellular models of toxicity via regulation of mitochondrial function. The objective of this study was to evaluate the effects of CO on APAP‐induced hepatotoxicity and CO's relationship to regulation of endoplasmic reticulum (ER) stress and mitochondrial signaling using CO‐releasing molecules or low concentrations of CO applied as pretreatment or post‐treatment. Using genetic deletion or knockdown approaches in alpha mouse liver cells or primary hepatocytes, respectively, we investigated the role of HO‐1 and the mitophagy regulator protein Parkin on APAP‐induced expression of the ER stress‐associated apoptosis regulator cytosine‐cytosine‐adenosine‐adenosine‐thymidine (CCAAT)/enhancer‐binding protein homologous protein (CHOP). We found that CO induced Parkin expression in hepatocytes via the protein kinase RNA‐like ER kinase/eukaryotic translation initiation factor 2‐α/activating transcription factor‐4 signaling pathway. Additionally, CO gas inhalation significantly alleviated APAP‐induced liver damage in vivo and correspondingly reduced serum alanine aminotransferase and aspartate aminotransferase levels as well as proinflammatory cytokines and reduced the expression of CHOP in liver tissues while dramatically increasing hepatic HO‐1 and Parkin expression. We found that the protective effects of CO on APAP‐induced liver damage were mediated by down‐regulation of CHOP at a transcriptional and post‐translational level via induction of HO‐1 and Parkin, respectively, and associated with decreases in reactive oxygen species production and JNK phosphorylation. We conclude that CO may represent a promising therapeutic agent for APAP‐induced liver injury.—Chen, Y., Park, H.‐J., Park, J., Song, H.‐C., Ryter, S. W., Surh, Y.‐J., Kim, U.‐H., Joe, Y., Chung, H. T. Carbon monoxide ameliorates acetaminophen‐induced liver injury by increasing hepatic HO‐1 and Parkin expression. FASEB J. 33, 13905‐13919 (2019). www.fasebj.org