Abstract
Background and aimsNonalcoholic Steatohepatitis (NASH) is a major cause of end-stage liver diseases such as cirrhosis and hepatocellular carcinoma resulting ultimately in increased liver-related mortality. Fibrosis is the main driver of mortality in NASH. Procollagen C-Proteinase Enhancer-1 (PCPE-1) plays a key role in procollagen maturation and collagen fibril formation. To assess its role in liver fibrosis and NASH progression, knock-out mice were evaluated in a dietary NASH model.MethodsGlobal constitutive Pcolce-/- and WT male mice were fed with a Choline Deficient Amino acid defined High Fat Diet (CDA HFD) for 8 weeks. Liver triglycerides, steatosis, inflammation and fibrosis were assessed at histological, biochemical and gene expression levels. In addition, human liver samples from control and NASH patients were used to evaluate the expression of PCPE-1 at both mRNA and protein levels.ResultsPcolce gene deficiency prevented diet-induced liver enlargement but not liver dysfunction. Furthermore, liver triglycerides, steatosis and inflammation were not modified in Pcolce-/- male mice compared to WT under CDA HFD. However, a significant decrease in liver fibrosis was observed in Pcolce-/- mice compared to WT under NASH diet, associated with a decrease in total and insoluble collagen content without any significant modifications in the expression of genes involved in fibrosis and extracellular matrix remodeling. Finally, PCPE-1 protein expression was increased in cirrhotic liver samples from both NASH and Hepatitis C patients.ConclusionsPcolce deficiency limits fibrosis but not NASH progression in CDA HFD fed mice.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is a common and progressive disease mainly characterized by hepatic fat accumulation in the absence of alcohol consumption
A significant decrease in liver fibrosis was observed in Pcolce-/- mice compared to WT under nonalcoholic steatohepatitis (NASH) diet, associated with a decrease in total and insoluble collagen content without any significant modifications in the expression of genes involved in fibrosis and extracellular matrix remodeling
In order to address the role of Procollagen C-Proteinase Enhancer-1 (PCPE-1) in the development of NASH and liver fibrosis, we first evaluated its expression in different preclinical murine models of NASH
Summary
Nonalcoholic fatty liver disease (NAFLD) is a common and progressive disease mainly characterized by hepatic fat accumulation in the absence of alcohol consumption. The ECM is a complex network of proteins including fibrillar and non-fibrillar collagens, glycosaminoglycans, proteoglycans and non-collagenous glycoproteins This so-called matrisome composition may change with liver injury [7]. Aging has been shown to enhance liver fibrotic response in mice through the impairment of extracellular matrix remodeling [8]. All of these studies underline the importance of better characterizing the matrisome and its remodeling during disease progression in order to identify potential drug targets. Nonalcoholic Steatohepatitis (NASH) is a major cause of end-stage liver diseases such as cirrhosis and hepatocellular carcinoma resulting in increased liver-related mortality. To assess its role in liver fibrosis and NASH progression, knock-out mice were evaluated in a dietary NASH model
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