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. 1. Introduction The atherosclerotic lesion is dominated by accumulation of lipid peroxides along with the progression of early plaque development [1]. Serum paraoxonase-1 (PON1) is an HDL-associated lipolactonase, which is synthesized and secreted by the liver [2]. PON1 has antioxidative properties, which are associated with the enzyme’s capability to protect LDL [3], as well as HDL [4] from oxidation, to decrease macrophage oxidative status [5], to stimulate cholesterol efflux from macrophages [6], to decrease oxidative status in atherosclerotic lesions [7], and to attenuate atherosclerosis development. Immunohistochemical analysis has revealed accumulation of PON1 in the human atherosclerotic lesion as it progresses from fatty streak to advanced lesion [8]. Recently it was demonstrated that PON1 acts to reduce the oxidizing potency of lipids in atherosclerotic lesions, thus providing protection against oxidation [9]. Epidemiological evidence demonstrates that low PON1 activity is associated with increased risk of cardiovascular events [10] and is an independent risk factor for cardiovascular disease [11]. A variety of nongenetic factors have been shown to influence serum PON1 levels and activity. PON1 undergoes inactivation under oxidative stress and its activity is preserved by dietary antioxidants [12]. Moderate daily consumption of alcohol [13], vitamin C and E [14], wine [15], or pomegranate juice [16], increased serum levels of PON1 in
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