Abstract
BackgroundParaoxonase-1 (PON1), a lactonase synthesized by the liver, circulates in blood bound to high-density lipoproteins (HDL). This enzyme is thought to degrade oxidized phospholipids and play an important role in the organism's antioxidant and anti-inflammatory system. Chronic liver diseases are characterized by decreased serum PON1 activity. The aim of the present study was to investigate the compositional changes in HDL that could influence PON1 activity in liver impairment.MethodsThe study was performed in samples from five patients with advanced liver cirrhosis and with preserved renal function, chosen on the basis of having low serum PON1 activity and high serum PON1 concentration. As a control group, we accessed five healthy volunteers from among our hospital staff. Lipid and protein compositional analysis of lipoprotein particles were done by high-performance liquid chromatography, gel electrophoresis, and Western-Blot.ResultsHDL particles from cirrhotic patients had an increased phospholipid content that was inversely correlated to PON1 activity. The HDL particles contained high levels of PON1 that corresponded, in part, to an immunoreactive protein of high molecular weight (55 kDa) not present in control subjects. This protein was identified as glycosylated PON1 and was also present in biopsies from patients with steatosis and from rats with CCl4-induced hepatic impairment. These changes were associated with an increased plasma concentration of markers of oxidative stress, inflammation and fibrogenesis.ConclusionAbnormalities in the composition of lipids and proteins of HDL particles, including PON1 glycosylation, are associated with the decrease in serum PON1 activity in patients with liver disease. These alterations may adversely affect the protective role of HDL against oxidative stress and inflammation in these patients.
Highlights
Paraoxonase-1 (PON1), a lactonase synthesized by the liver, circulates in blood bound to high-density lipoproteins (HDL)
Changes in liver function tests and serum lipoproteins Relative to the control group, the patients with chronic liver impairment had, as expected, a significant increase in serum aminotransferases and alkaline phosphatase activities together with a decrease in albumin, HDL-cholesterol, and apo A-I concentrations. They showed a profound decrease in serum PON1 activity and an increase in PON1 concentration, together with an increase in total peroxides, monocyte chemoattractant protein-1 (MCP-1), and type III procollagen-N-peptide (P-III-P) concentrations (Table 1)
Albumin; g/L Alanine aminotransferase; μkat/L Aspartate aminotransferase; μkat/L γ-glutamyl transferase; μkat/L Alkaline phosphatase; μkat/L Bilirubin; μmol/L Total peroxides: μmol/L Monocyte chemoattractant protein-1; ng/L Type III procollagen-N-peptide; μg/L Paraoxonase-1 activity; U/L Paraoxonase-1 concentration; mg/L Cholesterol; mmol/L Free cholesterol; mmol/L Triglycerides; mmol/L Phospholipids; mmol/L HDL-cholesterol; mmol/L Apolipoprotein A-I; g/L Apolipoprotein A-II; g/L Apolipoprotein E; mg/L Values are expressed as means and SD
Summary
Paraoxonase-1 (PON1), a lactonase synthesized by the liver, circulates in blood bound to high-density lipoproteins (HDL). This enzyme is thought to degrade oxidized phospholipids and play an important role in the organism's antioxidant and anti-inflammatory system. Chronic liver diseases are characterized by decreased serum PON1 activity. The aim of the present study was to investigate the compositional changes in HDL that could influence PON1 activity in liver impairment. Paraoxonase-1 (PON1) is an esterase and lactonase that is found in the circulation bound to high-density lipoproteins (HDL) [1]. PON1 is thought to degrade oxidized phospholipids in lipoproteins and play an important role in the organism's antioxidant system [3,4]. Recent studies in healthy volunteers showed a close relationship between circulating HDL levels and the inflammatory response to endotoxin challenge; the incidence and severity of clinical symptoms and the plasma concentrations of tumor necrosis factor, interleukins 1, 6 and 8, and monocyte chemoattractant protein-1 (MCP-1) being higher in subjects with low HDL than in those with
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