Increased Autophagy and Liver Regeneration Protects Lipocalin 2 Knockout Mice from Acetaminophen-induced Acute Liver Failure
Date of Award
Master of Science in Biomedical Sciences
Vishakha Bhave, BS, PhD
Francis E. Jenney, Jr., PhD
Shashidharamurthy Taval, PhD
Xinyu (Eric) Wang, PhD
Richard White, PhD, FAHA
Acetaminophen (AP AP) overdose is the most common cause of Acute Liver Failure (ALF) in the US. Following AP AP overdose, toxicity is initiated by the conversion of AP AP to its reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), which binds covalently to mitochondrial proteins leading to centrilobular necrosis and sterile inflammation. Lipocalin-2 (LCN2), an acute-phase innate immune protein, is upregulated during tissue injury in various organs including the liver. Recent data from our lab indicates that LCN2 KO mice are protected against ALF caused by AP AP-overdose compared to WT mice. This protection is not due to decreased bioactivation-based initial injury, but due to differences in the progressive phase of liver injury at later time points (24-48hr). LCN2 KO mice exhibit significantly less hepatocellular damage (ALT and histopathology) and higher liver regeneration response post AP AP overdose. However, the mechanistic functions of LCN2 in ALF resulting from AP AP overdose remains ambiguous and is the objective of the present study. During AP AP-induced necrosis, hepatocytes release Damage Associated Molecular Patterns, one of which is High Mobility Group Box 1 (HMGB 1 ). HMGB 1 can have a protective or damaging role based on its location in the nucleus, cytoplasm, or extracellularly. Cytoplasmic HMGB 1 binding to Beclin-1 and induces a favorable autophagic response to support liver regeneration. We hypothesize that causative relationships between HMGBl, Beclin-1, and LCN2 play a role in mediating progression of injury. HMGB 1 and Beclin 1 in WT and KO mice subjected to AP AP overdose ( 400 mg/kg) were assessed by immunoprecipitation and western blot over a time course. The difference in susceptibility between WT and LCN2 KO is due to (1) significantly increased autophagic response at 6hrs in KO mice and (2) increased rate of liver regeneration in KO mice at 48hrs as compared to WT mice. Consequently, increased autophagy in KO mice as compared to WT mice may be one of the mechanisms for protection against AP AP-induced ALF. Future directions will continue to identify novel pathways involving LCN2 and potentially recognize targets to attenuate/prevent the progression ofliver injury leading to ALF in APAP overdose cases.
Okaro, Christine J., "Increased Autophagy and Liver Regeneration Protects Lipocalin 2 Knockout Mice from Acetaminophen-induced Acute Liver Failure" (2019). PCOM Biomedical Studies Student Scholarship. 161.