Abstract
WDR13 - a WD repeat protein, is abundant in pancreas, liver, ovary and testis. Absence of this protein in mice has been seen to be associated with pancreatic β-cell proliferation, hyperinsulinemia and age dependent mild obesity. Previously, we have reported that the absence of WDR13 in diabetic Leprdb/db mice helps in amelioration of fatty liver phenotype along with diabetes and systemic inflammation. This intrigued us to study direct liver injury and hepatic regeneration in Wdr13−/0 mice using hepatotoxin CCl4. In the present study we report slower hepatic regeneration in Wdr13−/0 mice as compared to their wild type littermates after CCl4 administration. Interestingly, during the regeneration phase, hepatic hypertriglyceridemia was observed in Wdr13−/0 mice. Further analyses revealed an upregulation of PPAR pathway in the liver of CCl4- administered Wdr13−/0 mice, causing de novo lipogenesis. The slower hepatic regeneration observed in CCl4 administered Wdr13−/0 mice, may be linked to liver hypertriglyceridemia because of activation of PPAR pathway.
Highlights
Liver is a vital organ responsible for several metabolic processes and over 1 million deaths worldwide were reported from liver cirrhosis in 2010 [1]
Effect of Wdr13 deletion on liver pathology and regeneration after Carbon tetrachloride (CCl4) administration CCl4 damages the plasma membranes of hepatocytes, which leads to increase in serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamate-pyruvate transaminase (SGPT) levels [12]
To analyse the damage caused by chronic CCl4 administration, we studied the liver damage parameters, namely; SGOT & SGPT, hepatocytes morphology, collagen deposition, lipid peroxidation and inflammation in WD repeat domain 13 (WDR13) deficient mice
Summary
Liver is a vital organ responsible for several metabolic processes and over 1 million deaths worldwide were reported from liver cirrhosis in 2010 [1]. Liver, being one of the fastest regenerating organs [2], rectifies the damage and, in the repair process accumulates extracellular matrix (collagen) resulting in fibrosis [3] causing morphologically and functionally damaged liver [3]. CCl4 gets metabolized to CCl3OO* peroxide free radicals in the liver via mitochondrial cytochrome P450 (CYP450) and the generated peroxide free radicals damage the hepatocyte lipid biomembrane, through lipid peroxidation, resulting in the release of cellular contents in extracellular matrix, eliciting a myriad of inflammatory signals in liver. High level of inflammation leads to apoptosis and further liver damage [6] These damages are, spontaneously reversible if the mice are given a regeneration period of 20 days [7]
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