Metabolic modulation of acetaminophen-induced hepatotoxicity by osteopontin

Cell Mol Immunol. 2019 May;16(5):483-494. doi: 10.1038/s41423-018-0033-z. Epub 2018 May 7.


Induction of osteopontin (OPN), a well-known pro-inflammatory molecule, has been observed in acetaminophen (APAP)-induced hepatotoxicity. However, the precise cell source for OPN induction and its role during APAP-induced hepatotoxicity has not been fully explored. By employing a hepatotoxic mouse model induced by APAP overdose, we demonstrate that both serum and hepatic OPN levels were significantly elevated in response to APAP treatment. Our in vivo and in vitro studies clearly indicated that the induced expression of hepatic OPN was mainly located in necrosis areas and produced by dying or dead hepatocytes. Functional experiments showed that OPN deficiency protected against the APAP-induced liver injury by inhibiting the toxic APAP metabolism via reducing the expression of the cytochrome P450 family 2 subfamily E member 1 (CYP2E1). Interestingly, this inhibition of CYP2E1 expression did not occur in unfasted Opn-/- mice, but was significant in fasted Opn-/- mice and maintained for 2 hours after APAP challenge in fasted Opn-/- mice. In addition, despite the early protective role of OPN deficiency on APAP-induced hepatotoxicity, OPN deficiency retarded injury resolution by sensitizing hepatocytes to apoptosis and impairing liver regeneration. Finally, we demonstrated that a siRNA-mediated transient hepatic Opn knockdown could sufficiently and significantly protect animals from APAP-induced hepatotoxicity and death. In conclusion, this study clearly defines the cell source of OPN induction in response to APAP treatment, provides a novel insight into the metabolic role of OPN to APAP overdose, and suggests an Opn-targeted therapeutic strategy for the treatment or prevention of APAP-induced hepatotoxicity.

Keywords: CYP2E1; acetaminophen; hepatotoxicity; ketone body; osteopontin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / adverse effects*
  • Animals
  • Apoptosis
  • Cells, Cultured
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Cytochrome P-450 CYP2E1 / genetics
  • Cytochrome P-450 CYP2E1 / metabolism
  • Disease Models, Animal
  • Drug Overdose / metabolism*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Hepatocytes / pathology
  • Humans
  • Liver / pathology*
  • Liver Regeneration
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Necrosis
  • Osteopontin / genetics
  • Osteopontin / metabolism*
  • RNA, Small Interfering / genetics
  • Up-Regulation


  • RNA, Small Interfering
  • Osteopontin
  • Acetaminophen
  • Cytochrome P-450 CYP2E1