Potential contribution of oxysterols and cholestanol in the vascular inflammatory process occurring in patients with Behcet's disease.

Abstract

Oxysterols, which are cholesterol oxidation products, can be generated by either enzymatic reactions and/or reactive oxygen species (ROS). Oxysterols considered to play key roles in health and diseases, have several physiological and biological activities. They exhibit strong immune-modulatory, pro-inflammatory and pro-oxidant properties supporting that some of them are involved in the pathogenesis of numerous chronic diseases associated with inflammation mainly cardiovascular and neurological diseases. Some oxysterols, especially those oxidized on the lateral chain, can bind to nuclear receptors such as the liver X receptors (LXR) involved in the control of transcriptional programs that regulate cell metabolism. Since Behçet's disease (BD) is an acute systemic vasculitis leading to severe vascular damage, recent studies deem that BD could be considered a chronic immune inflammatory disease. Although BD constitutes a separate disease entity, it is still underdiagnosed, and no treatments are available. Whereas the pathophysiology of BD is not well known, the vasculitis is common to its different etiologies. Therefore, as several oxysterols are known to contribute to vascular damage, these molecules were analyzed in the plasma of BD patients. Noteworthy, altered oxysterol profiles were observed in BD patients from Tunisia. These patients were characterized by abnormal levels of 7-ketocholesterol (7KC), 25-hydroxycholesterol (25-OHC), 27-hydroxycholesterol (27-OHC), and cholestane-3β,5α,6β-triol (CT). Thus, 7KC and 25-OHC were decreased whereas 27-OHC and CT were increased. Cholesterol undergoes a rapid non enzymatic oxidation to form cholesterol-5α,6α-epoxide and cholesterol-5β,6β-epoxide, and these molecules are then converted by cholesterol 5,6 epoxide hydrolase (ChEH) and/or ROS to CT. In addition, cholestanol level was increased. Therefore, there are evidence of altered oxysterol profiles and cholestanol level in BD patients. It is proposed that oxysterols and cholestanol could be used as biomarkers to characterize BD disease i) to distinguish different forms of this disease and of its outcome, and ii) to identify efficient treatments. Based on the abnormal levels of oxysterols and cholestanol observed in the plasma of BD Tunisian patients, current data support that a rupture of oxysterol homeostasis and perturbations of cholesterol metabolism, suggested by increased cholestanol level, could both contribute to the pathophysiology of Behçet's disease.