Impaired expression of the peroxisome proliferator–activated receptor alpha during hepatitis C virus infection

Background & Aims: Liver inflammation, fibrosis, and dyslipidemia are common features in patients with chronic hepatitis C virus (HCV) infection. Because peroxisome proliferator-activated receptor α (PPARα) is highly expressed in the liver and is involved in the regulation of lipid metabolism and inflammation, we sought to determine whether HCV infection may locally impair PPARα expression and activity. Methods: PPARα expression was investigated in liver biopsy specimens of 86 untreated patients with HCV infection and controls, by using real-time polymerase chain reaction (PCR), Western blot analysis, and immunohistochemistry. PPARα activity was assessed by quantification of the key gene target carnitine palmitoyl acyl-CoA transferase 1 (CPT1A) messenger RNA (mRNA).The influence of HCV core protein on PPARα mRNA expression was analyzed in vitro by real-time PCR in HCV core-expressing HepG2 cells activated with the PPARα ligand fenofibric acid. Results: Hepatic concentrations of PPARα and CPT1A expressed by hepatocytes were impaired profoundly in the livers of untreated patients with HCV infection compared with controls. A mean decrease of 85% in PPARα mRNA expression paralleled with a lack of CPT1A mRNA induction also were observed in HCV core-expressing HepG2 cells compared with controls. Conclusions: HCV infection is related to altered expression and function of the anti-inflammatory nuclear receptor PPARα. These results identify hepatic PPARα as one mechanism underlying the pathogenesis of HCV infection, and as a new therapeutic target in traditional treatment of HCV-induced liver injury.

Abbreviations used in this paper:  CPT1A, carnitine palmitoyl acyl-CoA transferase 1 , LXR, liver X receptor , PCR, polymerase chain reaction , PPAR, peroxisome proliferator activated receptor , RXR, retinoid X receptor