Oxysterols: Formation and biological function

Abstract

The association between plasma cholesterol (CHOL) and atherosclerosis has been a topic of research for many decades and continues to be a major Weld of investigation (McNamara, 2000; Kromhout, 2001). A considerable number of studies, both in animals and humans, have provided evidence that prolonged high levels of plasma CHOL increase the risk of developing atherosclerosis. However, the mechanisms by which CHOL contributes to the initiation and progression of atherosclerosis are still the subject of intense research. The observation that oxidized low-density lipoprotein (LDL) triggers early steps in atherogenesis (Steinberg et al., 1989; Ross, 1993) has focused attention on the role(s) of oxidizable components of LDL [namely the polyunsaturated fatty acid (PUFA) content], and the involvement of antioxidant vitamins, such as vitamins C and E and the carotenoids (especially b-carotene) in the prevention of cardiovascular diseases (Gey et al., 1991, 1993; Kushi et al., 1996). A number of compounds have been identiWed in oxidatively-modiWed LDL that elicit the development of atherosclerosis (Ross, 1999) and fatty streak formation (Lusis, 2000). In several cases, the compounds arise from oxidized lipids, including CHOL oxidation products or oxysterols (OS). When LDL is oxidized, the associated PUFA content is reduced, and the levels of lipid peroxides, aldehydes and OS increase (Patel et al., 1996; Chang et al., 1997). Several OS are of interest as possible reactive mediators of the structural and functional changes of the vascular system that are characteristic of the atherosclerotic process (Sevanian et al., 1995; Smith, 1996; Guardiola et al., 1996; Brown and Jessup, 1999; Russell, 2000; Schroepfer, 2000; Leonarduzzi et al., 2002). OS may also be linked to a wide range of other biological eVects in humans and animals, including cytotoxicity, mutagenesis, carcinogenesis, necrosis, apoptosis, immunosuppression and the development of gallstones (Brown and Jessup, 1999; Lyons and Brown, 1999; Lizard et al., 2000; Schroepfer, 2000; Bjorkhem and Diczfalusy, 2002). On the other hand, OS may regulate the expression of genes that participate in the metabolism of both sterols and fats, are intermediates in the transfer of sterols from the periphery to the liver and serve as substrates for the synthesis of bile acids (Russell, 2000). However, the mechanistic details and the identity of some of the native OS species have not been established with certainty.