Paraoxonase-1 is associated with oxidative stress, fibrosis and FAS expression in chronic liver diseases
Introduction
The generation of reactive oxygen species and the increase in hepatic lipid peroxidation are important features of chronic liver diseases [1], and oxidative stress is thought to be among the factors activating liver cell apoptosis [2], [3]. Particularly, this has been reported in hepatitis C infection, alcoholic liver disease, non alcoholic steatohepatitis, and acute liver failure [4], [5], [6]. The apoptotic process is characterized by a complete and active destruction of cellular proteins and DNA produced by a group of proteases, called caspases [7]. Caspase activation is regulated by membrane death receptors, able to induce an apoptotic signal when they are ligated to their ligands [8]. The predominant death receptor in liver tissue is FAS, a member of the tumor necrosis factor-receptor superfamily [9]. There is also a soluble form of FAS (sFAS), and patients with chronic liver diseases tend to have increased plasma concentrations of this compound [10], [11], [12]. Some studies suggest that sFAS down-regulates the apoptotic process by competition with the actual FAS ligand [13].
Recent studies suggest that high-density lipoproteins (HDL), which have antioxidant properties, may also have an antiapoptotic function [14], [15]. Paraoxonase 1 (PON1) is a hydrolase located on HDL [16] which has been postulated to play a protective effect on low-density lipoprotein oxidation [17]. PON1 has also been described to protect HDL from oxidation, and it is likely to be related to the attributed HDL antiapoptotic function, since the ability of HDL to protect against apoptosis is completely lost when the lipoprotein is oxidized [18]. We have previously shown that PON1 activity is significantly decreased in patients with chronic hepatitis or liver cirrhosis [19]. In the present study, we have further explored the relationship between PON1 and hepatic alterations, using available markers of fibrosis, serum sFAS concentration, and hepatic FAS expression.
Section snippets
Patients
Ninety-three patients with chronic liver diseases were consecutively recruited from those attending the outpatient clinics of the Hospital Universitari de Sant Joan between 2003 and 2005. In 82 cases (88%), liver biopsy was performed at the time of recruitment as required by their referring physician. The remaining 11 patients were diagnosed with liver cirrhosis on the basis of complete clinical exploration, including echography to evaluate splenomegaly or portal vein dilation and
Relationship between serum PON1 activity, concentration, and the degree of liver damage
We did not observe any major alteration in the liver function tests or in HDL cholesterol concentration in any of the patients' groups, indicating that, in general terms, our patients were well controlled and had a good clinical condition (Table 1). However, there were marked differences in the serum concentrations of P-III-P, fibronectin and laminin (P < 0.001, P = 0.023 and P = 0.005, respectively) in these patients, suggesting an increased severity in liver fibrosis. We also observed a significant
Discussion
We previously reported that serum PON1 activity may add relevant clinical information to the evaluation of chronic liver diseases [19]. In the present study, we have found that, despite the fact that liver function tests were not grossly altered in our patients, there were significant changes in PON1 related to histological alterations and circulating markers of fibrosis. Although we previously thought that the decrease in PON1 activity was secondary to an impaired synthesis of the enzyme, this
Acknowledgements
This study was supported by the Red de Centros de Metabolismo y Nutrición (RCMN C03/08) and the Fondo de Investigación Sanitaria (FIS 00/0252 and FIS 02/0430) from the Instituto de Salud Carlos III, Madrid, Spain. Natàlia Ferré is a researcher from the Juan de la Cierva program, Ministerio de Educación y Ciencia, Madrid. Judit Marsillach and Mònica Tous were recipients of grants from the Generalitat de Catalunya (FI 05/00068 and FI 02/00806, repectively).
References (45)
- et al.
Oxidative lipidomics of apoptosis: redox catalytic interactions of cytochrome C with cardiolipin and phosphatidylserine
Free Radic Biol Med
(2004) - et al.
Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis
Gastroenterology
(2003) Apoptotic pathways: the roads to ruin
Cell
(1998)- et al.
Purification and molecular cloning of the APO-1 cell surface antigen, a member of the tumour necrosis factor/nerve growth factor receptor superfamily
J Biol Chem
(1992) - et al.
Raised plasma soluble Fas and Fas-ligand in alcoholic liver disease
Lancet
(1998) - et al.
Serum levels of soluble Fas antigen in chronic hepatitis C patients
J Hepatol
(1998) - et al.
HDL and arteriosclerosis: beyond reverse cholesterol transport
Atherosclerosis
(2002) - et al.
High-density lipoprotens protect endothelial cells from tumor necrosis factor-α-induced apoptosis
Biochem Biophys Res Commun
(2000) - et al.
Biochemical markers of hepatic fibrosis
Clin Biochem
(1991) - et al.
Inhibition of hepatic cell nuclear DNA fragmentation by zinc in carbon tetrachloride-treated rats
J Hepatol
(1999)