Farnesyltransferase Inhibitor, Tipifarnib, Prevents Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure

Abstract

Acute liver failure (ALF) is a fatal syndrome associated with massive hepatocyte death. There is no cure for ALF except liver transplantation. Protein farnesylation is a lipid modification of cysteine residues that is catalyzed by farnesyltransferase (FTase) and has been proposed as an integral component of acute inflammation. Previously, we have demonstrated that FTase inhibitors improve survival in mouse models of endotoxemia and sepsis. Here we studied the effects of FTase inhibitor, tipifarnib, on galactosamine (GalN) /lipopolysaccharide (LPS)-induced acute liver failure. The effects of tipifarnib (10 mg/kg, IP) were studied in GalN (400 mg/kg, IP) and LPS (3 μg/kg)-challenged mice by histological and biochemical analyses. GalN/LPS administration caused prominent liver injury characterized by the increased plasma alanine aminotransferase (ALT) and aspartic aminotransferase (AST) levels leading to significant mortality in mice. Tipifarnib inhibited GalN/LPS-induced caspase 3 activation, inflammatory cytokine production, and c-Jun N-terminal Kinase (JNK) phosphorylation in the liver. On the other hand, Tipifarnib upregulated anti-apoptotic protein, Bcl-xL, in the liver after GalN/LPS challenge. Tipifarnib also protected primary hepatocytes from GalN/tumor necrosis factor-α (TNF-α)-induced cell death by inhibiting caspase 3 activation and upregulating anti-apoptotic proteins. GalN/LPS-induced liver injury was associated with increased protein farnesylation in the liver. Tipifarnib prevented protein farnesylation in the liver and markedly attenuated liver injury and mortality in GalN/LPS-challenged mice. These results suggest that protein farnesylation is a novel potential molecular target to prevent hepatocyte death and acute inflammatory liver failure in fulminant hepatitis.

Nuclear Receptor Subfamily 1 Group D Member 1 Regulates Circadian Activity of NLRP3 Inflammasome to Reduce the Severity of Fulminant Hepatitis in Mice

“…Low doses of LPS in combination with the specific hepatotoxic agent D-galactosamine (GalN) promote specific liver injury in mice and induce the production of inflammatory cytokines (TNF-α, IL1B and IL-6) 39 thus recapitulating the clinical picture of acute liver injury in humans 39 . For these reasons, the LPS/GalN-induced hepatic injury is a widely used mouse model to understand fulminant hepatitis and its pharmacological treatment 39–41 . Because the clock machinery controls the circadian behavior of the immune system, we hypothesized that the outcome of fulminant hepatitis may depend on the time of hepatitis induction.…”

Role of the microRNA‑214/Bax axis in the progression of acute liver failure

“…Furthermore, 2 major mechanisms of cell death, namely the death receptor pathway and the mitochondrial pathway, are involved in the progression of alF, in which TnF serves a crucial role (25). The caspase family is a key contributor to cell apoptosis, and it has been reported that caspase-3 is significantly activated in the ALF model (26). in addition, apoptotic-associated proteins tightly control cell apoptosis (27).…”

New tricks for human farnesyltransferase inhibitor: cancer and beyond

“…Tipifarnib (2) prevented protein farnesylation in the liver and markedly attenuated liver injury and mortality in galactosamine (GalN)-lipopolysaccharide (LPS)challenged mice by inhibiting GalN-LPS-induced caspase 3 activation, inflammatory cytokine production and c-Jun N-terminal kinase (JNK) phosphorylation in the liver, upregulating anti-apoptotic protein Bcl-xL, and protecting primary hepatocytes from GalN/tumor necrosis factor-α (TNF-α)induced cell death. 126…”