Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection.
OBJECTIVE
Liver inflammation, fibrosis, and dyslipidemia are common features in patients with chronic hepatitis C virus (HCV) infection. Because peroxisome proliferator-activated receptor alpha (PPARalpha) 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 PPARalpha expression and activity.


METHODS
PPARalpha 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. PPARalpha 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 PPARalpha mRNA expression was analyzed in vitro by real-time PCR in HCV core-expressing HepG2 cells activated with the PPARalpha ligand fenofibric acid.


RESULTS
Hepatic concentrations of PPARalpha 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 PPARalpha 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 PPARalpha. These results identify hepatic PPARalpha as one mechanism underlying the pathogenesis of HCV infection, and as a new therapeutic target in traditional treatment of HCV-induced liver injury.
Dharancy
Sébastien
S
Equipe Mixte INSERM 0114, Centre Hospitalier Universitaire, Lille, France.
Malapel
Mathilde
M
Perlemuter
Gabriel
G
Roskams
Tania
T
Cheng
Yang
Y
Dubuquoy
Laurent
L
Podevin
Philippe
P
Conti
Filoména
F
Canva
Valérie
V
Philippe
David
D
Gambiez
Luc
L
Mathurin
Philippe
P
Paris
Jean-Claude
JC
Schoonjans
Kristina
K
Calmus
Yvon
Y
Pol
Stanislas
S
Auwerx
Johan
J
Desreumaux
Pierre
P
D001706:Biopsy; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D017931:DNA Primers; D011345:Fenofibrate / Q000031:analogs & derivatives* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms; D047493:PPAR alpha / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D017931:DNA Primers; D047493:PPAR alpha; C006012:fenofibric acid; D011345:Fenofibrate