Paraoxonase-1 is related to inflammation, fibrosis and PPARδ in experimental liver disease

Centre de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut d'Investigacions Sanitàries Pere Virgili, Universitat Rovira i Virgili, C, Sant Joan s/n, 43201 Reus, Spain.
BMC Gastroenterology (Impact Factor: 2.37). 02/2009; 9(1):3. DOI: 10.1186/1471-230X-9-3
Source: PubMed


Paraoxonase-1 (PON1) is an antioxidant enzyme synthesized by the liver. It protects against liver impairment and attenuates the production of the pro-inflammatory monocyte chemoattractant protein-1 (MCP-1). We investigated the relationships between hepatic PON1 and MCP-1 expression in rats with liver disease and explored the possible molecular mechanisms involved.
CCl4 was administered for up to 12 weeks to induce liver damage. Serum and hepatic levels of PON1 and MCP-1, their gene and protein expression, nuclear transcription factors, and histological and biochemical markers of liver impairment were measured.
High levels of PON1 and MCP-1 expression were observed at 12th week in the hepatocytes surrounding the fibrous septa and inflammatory areas. CCl4-administered rats had an increased hepatic PON1 concentration that was related to decreased gene transcription and inhibited protein degradation. Decreased PON1 gene transcription was associated with PPARdelta expression. These changes were accompanied by increased hepatic MCP-1 concentration and gene expression. There were significant direct relationships between hepatic PON1 and MCP-1 concentrations (P = 0.005) and between PON1 and the amount of activated stellate cells (P = 0.001).
Our results from this experimental model suggest a hepato-protective role for PON1 against inflammation, fibrosis and liver disease mediated by MCP-1.

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    • "As mentioned earlier the liver plays a key role in the synthesis of PON1, and chronic liver diseases are associated with increased oxidative stress and inflammation [35]. PON1 protects liver against inflammation, liver disease and fibrosis [36]. We could not detect any significance differences between NAFLD patients and controls in PON1 and salt-stimulated PON1 activities. "
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    ABSTRACT: The aim of the study was to investigate paraoxonase-1 (PON1) and aryl esterase (ARE) activities in patients with nonalcoholic fatty liver disease (NAFLD). This case-control study was done on 83 subjects with confirmed NAFLD (50 male, 33 female, age; 40.46±12.13 years) and 138 healthy individuals (75 male, 63 female; age; 40.94±14.50 years). PON1, salt-stimulated PON1 and ARE activities were determined using paraoxon and phenyl acetate as substrate, respectively. The levels of PON1 activities in NAFLD and healthy individuals were 90.83±63.65 IU/L and 79.41±68.14 IU/L, respectively. There was no significant differences regarding PON1 activity between NAFLD and healthy subjects (p=0.229). While, ARE activity was significantly higher in NAFLD (83.34±28.36 KU/L) than in normal subjects (64.06±27.49 KU/L) (p<0.001). Our results showed that PON1 activity is not a promising biomarker for the evaluation of NAFLD while arylesterase may have, but further studies in larger samples with different ethnic groups are required to validate our findings.
    Full-text · Article · May 2012 · Pathophysiology
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    • "PON1 mRNA expression in hepatocytes was reduced also by oxidized phospholipids found in mildly oxidized LDL through the inflammatory cytokine IL-6, and IL-6 alone produced the same pattern of PON1 mRNA changes [21]. Liver damage induced by CCl 4 resulted in decreased PON1 gene transcription but increased hepatic PON1 concentration that was related to inhibited protein degradation [22]. Decreased PON1 gene transcription was associated with PPARδ expression. "
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    ABSTRACT: Serum paraoxonase-1 (PON1) is a member of the paraoxonases family (PON1, PON2, and PON3). PON1 is synthesized and secreted by the liver, and in circulation it is associated with HDL. PON1 has antioxidative properties, which are associated with the enzyme's capability to decrease oxidative stress in atherosclerotic lesions and to attenuate atherosclerosis development. Epidemiological evidence demonstrates that low PON1 activity is associated with increased risk of cardiovascular events and cardiovascular disease and is an independent risk factor for coronary artery disease. Therefore, pharmacological modulation of PON1 activity or PON1 gene expression could constitute a useful approach for preventing atherosclerosis. A primary determinant of serum PON1 levels is the availability of the enzyme for release by the liver, the principal site of PON1 production. Together with the enzyme secretion rate, enzymatic turnover, and protein stability, the level of PON1 gene expression is a major determinant of PON1 status. This paper summarizes recent progress in understanding the regulation of PON1 expression in hepatocytes.
    Full-text · Article · Apr 2012
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    • "Administration regimen was twice a week for six consecutive weeks. CCl4 (0.5 ml/kg) was suspended in olive oil (1:9 v/v) and injected intraperitoneally [23]. Ginger extracts were administrated orally at a dose 200 mg/kg) [14]. "
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    ABSTRACT: Zingiber officinale Roscoe (ginger) (Zingiberaceae) has been cultivated for thousands of years both as a spice and for medicinal purposes. Ginger rhizomes successive extracts (petroleum ether, chloroform and ethanol) were examined against liver fibrosis induced by carbon tetrachloride in rats. The evaluation was done through measuring antioxidant parameters; glutathione (GSH), total superoxide dismutase (SOD) and malondialdehyde (MDA). Liver marker enzymes; succinate and lactate dehydrogenases (SDH and LDH), glucose-6-phosphatase (G-6-Pase), acid phosphatase (AP), 5'- nucleotidase (5'NT) and liver function enzymes; aspartate and alanine aminotransferases (AST and ALT) as well as cholestatic markers; alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total bilirubin were estimated. Liver histopathological analysis and collagen content were also evaluated. Treatments with the selected extracts significantly increased GSH, SOD, SDH, LDH, G-6-Pase, AP and 5'NT. However, MDA, AST, ALT ALP, GGT and total bilirubin were significantly decreased. Extracts of ginger, particularly the ethanol one resulted in an attractive candidate for the treatment of liver fibrosis induced by CCl4. Further studies are required in order to identify the molecules responsible of the pharmacological activity.
    Full-text · Article · Jun 2011 · Nutrition & Metabolism
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