Abstract
Hepatitis-C-virus-related infective diseases are worldwide spread pathologies affecting primarily liver. The infection is often asymptomatic, but when chronically persisting can lead to liver scarring and ultimately to cirrhosis, which is generally apparent after decades. In some cases, cirrhosis will progress to develop liver failure, liver cancer, or life-threatening esophageal and gastric varices. HCV-infected cells undergo profound metabolic dysregulation whose mechanisms are yet not well understood. An emerging feature in the pathogenesis of the HCV-related disease is the setting of a pro-oxidative condition caused by dysfunctions of mitochondria which proved to be targets of viral proteins. This causes deregulation of mitochondria-dependent catabolic pathway including fatty acid oxidation. Nuclear receptors and their ligands are fundamental regulators of the liver metabolic homeostasis, which are disrupted following HCV infection. In this contest, specific attention has been focused on the peroxisome proliferator activated receptors given their role in controlling liver lipid metabolism and the availability of specific pharmacological drugs of potential therapeutic utilization. However, the reported role of PPARs in HCV infection provides conflicting results likely due to different species-specific contests. In this paper we summarize the current knowledge on this issue and offer a reconciling model based on mitochondria-related features.
Highlights
Hepatitis-C-virus-related infective diseases are worldwide spread pathologies affecting primarily liver
In this paper we summarize the current knowledge on this issue and offer a reconciling model based on mitochondria-related features
All these functions might contribute to the influence of peroxisome proliferator-activated receptors (PPARs) in carcinogenesis, whether PPARs function as tumor suppressor or as oncogenes in cancer is still unclear
Summary
The peroxisome proliferator-activated receptors (PPARs) are transcription factors that translate nutritional signals into specific gene-expression patterns that control cellular differentiation, development, metabolism (carbohydrate, lipid, protein), and tumorigenesis. Activation of PPARα leads to increased proliferation and inhibition of apoptosis and when this occurs in a DNA-damaged cells, it is thought to lead to proliferation of initiated cells that progress to a liver tumor This effect is supported by observation in PPARα-null mice that are refractory to all these changes in response to longterm ligand-feeding studies [25, 26]. The metabolic changes along with the anti-apoptotic effects of PPARs activation contribute to oxidative DNA damage and increase hepatocellular proliferation leading to liver cancer development [2, 28]. The study has shown that TGF-β regulates the growth of primary and transformed hepatocytes through concurrent activation of Smad-mediated gene transcription and phosphorylation of cPLA2α suggesting that the level and activation status of cPLA2α/PPAR-γ signaling in hepatic cells likely represents a key factor that determines the cellular response to TGF-β. The contribution of the hypoxia inducible factor (HIF1α) to the metabolic/bioenergetic adaptation by (normoxic) up-regulation of the glycolytic pathway is shown
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