Regeneration and Recovery after Acetaminophen Hepatotoxicity

Abstract

Liver regeneration is a compensatory response to tissue injury and loss. It is known that liver regeneration plays a crucial role in recovery following acetaminophen (APAP)-induced hepatotoxicity, which is the major cause of acute liver failure (ALF) in the US. Regeneration increases proportional to the extent of liver injury upon APAP overdose, ultimately leading to regression of injury and spontaneous recovery in most cases. However, severe APAP overdose results in impaired liver regeneration and unchecked progression of liver injury, leading to failed recovery and mortality. Inter-communication between various cell types in the liver is important for effective regenerative response following APAP hepatotoxicity. Various non-parenchymal cells such macrophages, stellate cells, and endothelial cells produce mediators crucial for proliferation of hepatocytes. Liver regeneration is orchestrated by synchronized actions of several proliferative signaling pathways involving numerous kinases, nuclear receptors, transcription factors, transcriptional co-activators, which are activated by cytokines, growth factors, and endobiotics. Overt activation of anti-proliferative signaling pathways causes cell-cycle arrest and impaired liver regeneration after severe APAP overdose. Stimulating liver regeneration by activating proliferating signaling and suppressing anti-proliferative signaling in liver can prove to be important in developing novel therapeutics for APAP-induced ALF.

Keywords: Cyclin D1; TGFβ1; drug-induced liver injury; hepatotoxicity; liver regeneration; p21; proliferation; β-catenin.

Figure 1.

Schematics showing an overview of the process of liver regeneration and recovery following acetaminophen (APAP)-hepatotoxicity: APAP overdose initiates a cascade of events resulting in centrilobular liver necrosis. Pro-regenerative signals from various hepatic cell types stimulate hepatocyte proliferation and liver regeneration resulting in regression of liver injury and spontaneous recovery after moderate APAP overdose. Various anti-regenerative signals are also activated for balanced proliferative response and effective repair. However, overt activation of anti-proliferative pathways after severe APAP overdose results in impaired liver regeneration and failed recovery. GSH, glutathione; MPTP, mitochondrial permeability transition pore; NAPQI, N-acetyl-p-benzoquinone imine. Normal liver (top, left) and necrotic liver after acetaminophen-induced acute liver injury (top, right) are represented by respective hematoxylin and eosin (H&E)-stained liver sections; Regenerating liver (bottom) is represented by liver section with proliferating cell nuclear antigen (PCNA) positive hepatocytes (brown staining).