Impaired liver regeneration and lipid homeostasis in CCl 4 treated WDR13 deficient mice
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Laboratory Animal Research
RESEARCH
Open Access
Impaired liver regeneration and lipid homeostasis in CCl4 treated WDR13 deficient mice Arun Prakash Mishra* , Archana B. Siva, Chandrashekaran Gurunathan, Y. Komala and B. Jyothi Lakshmi
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. Keywords: Fatty liver, PPARg, Hepatosteatosis, Hypertriglyceridemia, Hepatotoxin
Introduction Liver is a vital organ responsible for several metabolic processes and over 1 million deaths worldwide were reported from liver cirrhosis in 2010 [1]. Several factors cause liver damage, of which chronic alcohol abuse and viral hepatitis are identified as the major ones [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]. Liver damage also occurs as a result of extensive lipid accumulation - popularly known as fatty liver, that is caused by either high fat diet intake or obesityassociated insulin resistance [non-alcohol dependent steatohepatitis or NASH] [4]. Hepatocyte damage induced by fatty liver condition leads to inflammation and fibrosis in liver [3]. * Correspondence: [email protected] CSIR- Centre for Cellular and Molecular Biology, Hyderabad 500007, India
To study liver damage in mouse model, chronic CCl4 (carbon tetrachloride) administration is an established method [5]. 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, however, spontaneously reversible if the mice are given a regeneration period of 20 days [7]. WDR13, a member of the WD repeat protein fa
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