Upregulation of calpastatin in regenerating and developing rat liver: Role in resistance against hepatotoxicity

Abstract

Acute liver failure induced by hepatotoxic drugs results from rapid progression of injury. Substantial research has shown that timely liver regeneration can prevent progression of injury leading to a favorable prognosis. However, the mechanism by which compensatory regeneration prevents progression of injury is not known. We have recently reported that calpain released from necrotic hepatocytes mediates progression of liver injury even after the hepatotoxic drug is cleared from the body. By examining expression of calpastatin (CAST), an endogenous inhibitor of calpain in three liver cell division models known to be resistant to hepatotoxicity, we tested the hypothesis that increased CAST in the dividing hepatocytes affords resistance against progression of injury. Liver regeneration that follows CCl 4 -induced liver injury, 70% partial hepatectomy, and postnatal liver development were used. In all three models, CAST was upregulated in the dividing/newly divided hepatocytes and declined to normal levels with the cessation of cell proliferation. To test whether CAST overexpression confers resistance against hepatotoxicity, CAST was overexpressed in the livers of normal SW mice using adenovirus before challenging them with acetaminophen (APAP) overdose. These mice exhibited markedly attenuated progression of liver injury and 57% survival. Whereas APAP-bioactivating enzymes and covalent binding of the APAP-derived reactive metabolites remained unaffected, degradation of calpain specific target substrates such as fodrin was significantly reduced in these mice. In conclusion, CAST overexpression could be used as a therapeutic strategy to prevent progression of liver injury where liver regeneration is severely hampered. (HEPATOLOGY 2006;44:379-388.)

Human Recombinant Vascular Endothelial Growth Factor Reduces Necrosis and Enhances Hepatocyte Regeneration in a Mouse Model of Acetaminophen Toxicity

“…Liver regeneration is thought to limit the progression of phase 2 injury (Limaye et al, 2006). Cumulatively, the data in the present study suggest that hrVEGF had dual effects: mitigation of toxicity and enhancement of hepatocyte regeneration.…”

“…It has been proposed that acute liver injury occurs in two phases: phase 1 or initiation and phase 2 or progression (Limaye et al, 2006). Liver regeneration is thought to limit the progression of phase 2 injury (Limaye et al, 2006).…”

An integrative genomic analysis identifies Bhmt2 as a diet-dependent genetic factor protecting against acetaminophen-induced liver toxicity

“…Many factors have been associated with susceptibility to APAPinduced liver injury, including: factors affecting metabolic activation or GSH-mediated detoxification (Bai and Cederbaum 2004;Guo et al 2004;Jia et al 2005;Welch et al 2005), the immune response and cytokine production (Hogaboam et al 2000;Ishida et al 2002Ishida et al , 2004Liu et al 2004), or enzymes regulating apoptosis (Limaye et al 2003(Limaye et al , 2006Bhave et al 2008). Global analyses of APAP-induced changes in gene expression (Reilly et al 2001) or cellular proteins (Qiu et al 1998;Ruepp et al 2002;Welch et al 2005) have also identified a vast array of other potential mediators.…”

Yes-associated protein is involved in proliferation and differentiation during postnatal liver development

“…During this postnatal development, the liver acquires an adult gene expression program, and expression of several drug-metabolizing enzymes, transporters, and other enzymes involved in major metabolic processes is initiated (7,10). Another striking feature of postnatal liver development is the increase in liver size due to extensive hepatic cell proliferation, which increases liver size to the adult liver weight-to-body weight ratio (1)(2)(3)12). The postnatal liver development period is unique because the mechanisms involved in hepatic cell proliferation and hepatic differentiation operate simultaneously during this period.…”