Liver Regeneration after Acetaminophen Hepatotoxicity: Mechanisms and Therapeutic Opportunities

Abstract

Acetaminophen (N-acetyl-para-aminophenol; APAP) overdose is the most common cause of acute liver failure in the Western world, with limited treatment opportunities. For years, research on APAP overdose has been focused on investigating the mechanisms of hepatotoxicity, with limited success in advancing therapeutic strategies. Acute liver injury after any insult, including APAP overdose, is followed by compensatory liver regeneration, which promotes recovery and is a crucial determinant of the final outcome. Liver regeneration after APAP-induced liver injury is dose dependent and impaired after severe APAP overdose. Although robust regenerative response is associated with spontaneous recovery and survival, impaired regeneration results in faster progression of injury and death after APAP overdose. APAP hepatotoxicity-induced liver regeneration involves a complex time- and dose-dependent interplay of several signaling mediators, including growth factors, cytokines, angiogenic factors, and other mitogenic pathways. Compared with the liver injury, which is established before most patients seek medical attention and has proved difficult to manipulate, liver regeneration can be potentially modulated even in late-stage APAP-induced acute liver failure. Despite recent efforts to study the mechanisms of liver regeneration after APAP-induced liver injury, more comprehensive research in this area is required, especially regarding factors that contribute to impaired regenerative response, to develop novel regenerative therapies for APAP-induced acute liver failure.

Figure 1

Three phases of acetaminophen (N-acetyl-para-aminophenol; APAP)-induced liver injury. Pathogenesis of APAP-induced liver injury, divided into three mechanistically interrelated but distinct phases: i) initiation (bioactivation of APAP and initial cell death), ii) injury progression (exacerbation of initial injury via extracellular mechanisms), and iii) recovery (compensatory liver regeneration and repair). CYP, cytochrome P-450; DAMP, damage-associated molecular pattern; GSH, glutathione; HMGB1, high-mobility group box protein 1; MAPK, mitogen-activated protein kinase; mitoDNA, mitochondrial DNA; MPTP, mitochondrial permeability transition pore; NAPQI, N-acetyl-p-benzoquinone imine.

Figure 2

Molecular mechanisms of regeneration after acetaminophen (N-acetyl-para-aminophenol; APAP)-induced liver injury. Liver regeneration after APAP overdose involves a complex time- and dose-dependent interplay of several signaling mediators. Several proliferative signaling pathways that control cell cycle machinery, including growth factor signaling via epidermal growth factor receptor (EGFR) and c-MET [receptor for hepatocyte growth factor (HGF)], cytokine signaling [tumor necrosis factor (TNF)-α/NF-κB and IL-6/STAT-3], Wnt/β-catenin, and bile acid signaling are activated after APAP overdose, potentially contributing to liver regeneration. Some of these proliferative signaling pathways including Wnt/β-catenin and TNF-α/NF-κB signaling are inhibited after severe APAP overdose (others such as EGFR/c-MET and IL-6/STAT-3 signaling remain activated), which is accompanied by unchecked DNA damage and activation of antiproliferative pathways [transforming growth factor (TGF)–β and p53/p21] leading to cell cycle arrest and impaired liver regeneration. Angiogenesis and the restoration of microvasculature during normal liver regeneration involve the activation of vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling, which also indirectly contributes to hepatocyte proliferation via the stimulation of HGF release from endothelial cells. Top, hematoxylin and eosin–stained liver sections that are normal (left) and necrotic (right). Bottom, regenerating liver, shown as proliferating cell nuclear antigen (PCNA)-positive hepatocytes (brown nuclear staining). FXR, farnesoid X receptor; Fzld, frizzled protein; G0, gap 0 phase; G1, gap 1 phase; G2, gap 2 phase; GSH, glutathione; GSK, glycogen synthase kinase; ILK, integrin-linked protein kinase; M, mitosis phase; MAPK, mitogen-activated protein kinase; NAPQI, N-acetyl-p-benzoquinone imine; S, synthesis phase; TNFR, TNF receptor.