Impaired liver regeneration and lipid homeostasis in CCl₄ treated WDR13 deficient mice

Abstract

15Background and Aim-WDR13 -a WD repeat protein, is abundant in pancreas, liver, ovary and 16 testis. Absence of this protein in mice has been seen to be associated with pancreatic -cell 17 proliferation, hyperinsulinemia and age dependent mild obesity. Previously, we have reported that 18 the absence of WDR13 in diabetic Lepr db/db mice helps in amelioration of fatty liver phenotype 19 along with diabetes and systemic inflammation. This intrigued us to study direct liver injury and 20 hepatic regeneration in Wdr13 -/0 mice using hepatotoxin CCl 4. 21Methods-Mice were injected with CCl 4 twice a week for 8 consecutive weeks. Controls were 22 injected with vehicle (olive oil) similarly. After the last injection, mice were given a 10-days of 23 recovery period and then sacrificed for physiological and molecular analyses. 24Results-In the present study we report slower hepatic regeneration in Wdr13 -/0 mice as compared 25 to their wild type littermates after CCl 4 administration. Interestingly, during the regeneration 26 phase, hepatic hypertriglyceridemia was observed in Wdr13 -/0 mice. Further analyses revealed an 27 upregulation of PPAR pathway in the liver of CCl 4 -administered Wdr13 -/0 mice, causing de novo 28 lipogenesis. 29 Conclusions-The slower hepatic regeneration observed in CCl 4 administered Wdr13 -/0 mice, may 30 be linked to liver hypertriglyceridemia because of activation of PPAR pathway. 33Liver is a vital organ responsible for several metabolic processes and over 2 million deaths per 34 year worldwide have been reported from liver related diseases [1]. Several factors cause liver 35 damage, of which chronic alcohol abuse and viral hepatitis are identified as the major ones [2]. 36 Liver, being one of the fastest regenerating organs [3], rectifies the damage and, in the repair 37 process accumulates extracellular matrix (collagen) resulting in fibrosis [4] causing 38 morphologically and functionally damaged liver [4]. Liver damage also occurs as a result of 39 extensive lipid accumulation -popularly known as fatty liver, that is caused by either high fat diet 40 intake or obesity-associated insulin resistance [non-alcohol dependent steatohepatitis or NASH] 41 [5]. Hepatocyte damage induced by fatty liver condition leads to inflammation and fibrosis in liver 42 [4]. 43To study liver damage in mouse model, chronic CCl 4 (carbon tetrachloride) administration is an 44 established method [6]. CCl 4 gets metabolized to CCl 3 OO * peroxide free radicals in the liver via 45 mitochondrial cytochrome P450 (CYP450) and the generated peroxide free radicals damage the 46 hepatocyte lipid biomembrane, through lipid peroxidation, resulting in the release of cellular 47 contents in extracellular matrix, eliciting a myriad of inflammatory signals in liver. High level of 48 inflammation leads to apoptosis and further liver damage [7]. These damages are, however, 49 spontaneously reversible if the mice are given a regeneration period of 20 days [8]. 50WDR13, a member of the WD repeat protein family, is presen...

Absence of WDR13 in p53-Null Mice Increases Longevity

“…Role of WDR13 in cell cycle regulation in different tissues has been attributed to PPARγ. Wdr13 −/0 mice is known to have a higher expression levels of PPARγ in adipose (8) and in liver (10). Activation of PPARγ slows the regeneration of liver in CCl 4 administered Wdr13 −/0 mice (10).…”

“…Wdr13 −/0 mice is known to have a higher expression levels of PPARγ in adipose (8) and in liver (10). Activation of PPARγ slows the regeneration of liver in CCl 4 administered Wdr13 −/0 mice (10). The promoter of Pparγ has an AP1 site and WDR13 is known to bind AP1 sites with c-Jun (8).…”

“…Earlier studies on WDR13 suggest its involvement in cell cycle regulation in different tissues like pancreas (7)(8)(9), liver (10) adipose (11), colon (12) and uterus (13). Wdr13 expression has also been reported in many human cancers like breast cancer, glioma, Ewing's sarcoma, lung cancer, melanoma, testes cancer, ovary teratocarcinoma, and urothelial cancer (Human protein atlas http://www.proteinatlas.org/ENSG00000101940-WDR13/cancer).…”

Molecular characterization of Wdr13 knockout female mice uteri: a model for human endometrial hyperplasia

“…Other than estradiol, several metabolic impairments are also responsible for the cause of EH condition 36,37 . Wdr13 mutant mice has shown impairment related to lipogenesis through PPAR pathway 13 . Future studies are required in understanding the molecular mechanisms behind rescue of the phenotype in DES treated Wdr13 −/− mice.…”

“…Wdr13 knockout mice under stress with CCl 4 showed increased lipogenesis and fatty liver condition. These mice also displayed hepatic hypertriglyceridemia through upregulation of PPAR pathway 13 . The phenotypic features like hyperinsulinemia, increased body and abdominal fat pad weights are known risk factors for EC 3 .…”