Elsevier

Metabolism

Volume 52, Issue 10, October 2003, Pages 1287-1294
Metabolism

Light, but not heavy alcohol drinking, stimulates paraoxonase by upregulating liver mRNA in rats and humans

https://doi.org/10.1016/S0026-0495(03)00191-4Get rights and content

Abstract

Paraoxonase 1 (PON) may contribute to the cardioprotective action of high-density lipoprotein (HDL) because it inhibits low-density lipoprotein (LDL) oxidation, a prerequisite for the onset of atherosclerosis. Because light drinking and heavy drinking have diametrically opposite effects on cardioprotection, we have determined the effects of ethanol dosage on rat serum PON activity and its hepatic expression. Furthermore, we have investigated PON activity and polymorphism in human light and heavy drinkers. Our results confirm that HDL-PON inhibited LDL oxidation, destroyed oxidized LDL, and inhibited its uptake by macrophages. Light ethanol feeding caused a 20% to 25% (P < .05) increase in PON activity in both serum and liver and a 59% (P < .001) increase in the level of liver PON mRNA compared with pair-fed control rats. In contrast, heavy ethanol feeding caused a 25% (P < .05) decrease in serum and liver PON activities with a 51% (P < .01) decrease in liver PON mRNA level. Light drinkers had a 395% (P < .001) higher, whereas heavy drinkers had a 45% (P < .001) lower serum PON activity compared with nondrinkers. Significantly, the number of homozygotes versus heterozygotes with respect to high or low activity PON phenotype was similar in all the groups. Therefore, we conclude that light drinking upregulates, whereas heavy drinking downregulates PON activity and its expression, irrespective of its genetic polymorphism.

Section snippets

Reagents

Culture medium Dulbecco’s modified Eagle’s medium (DMEM) (hi-glucose), heat inactivated fetal bovine serum, glutamine, and antibiotics were obtained from Life Technologies (Rockville, MD). Heparin (10,000 USP U/mL) was obtained from Elkin-Sinn (Cherry Hill, NJ). Dextran sulfate (50 kd) was obtained from Genzyme (Cambridge, MA). Diet components were from ICN Biomedicals (Costa Mesa, CA) or from Dyets (Bethlehem, PA). All other reagents and chemicals were of analytical grade.

Animals and feeding regimen

The humane use of

Protective effect of HDL-PON on the oxidative modification of LDL

Serum PON1 is tightly associated with HDL and inhibits oxidative modification of LDL. Thus, higher PON1 activity is thought to be beneficial in protecting against CAD, which is caused, in part, by high levels of oxLDL. Because the focus of this study is to understand the mechanism underlying the causal relationship between alcohol consumption and CAD, we have established an assay to measure LDL susceptibility to oxidation in various conditions. Thus, we performed copper sulfate-mediated LDL

Discussion

It is now well known that CAD is the principal cause of mortality and morbidity in developed countries, and several features of this metabolic disorder are due to the accumulation of oxLDL, the atherogenic lipoprotein, in the intimae of the arterial wall. On the other hand, HDL is antiatherogenic because of its ability to remove cholesterol from peripheral tissues to transport it to the liver for degradation, a process called reverse cholesterol transport. Another mechanism by which HDL acts as

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    Supported by Grant No. R01 AA13411-01 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

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