26 - Trafficking of cholesterol hydroperoxides to macrophage mitochondria: implications for atherogenesis under oxidative stress

Abstract

Under oxidative stress conditions associated with chronic inflammation and obesity, scavenger receptor-expressing macrophages in arterial subendothelial spaces can internalize oxidized low-density lipoprotein (oxLDL) in unregulated fashion, potentially giving rise to foam cell-containing atherosclerotic lesions (plaques). In addition to other oxidized lipids, oxLDL contains cholesterol oxides such as 7-hydroperoxide (7-OOH), 7-alcohol (7-OH), and 7-ketone (7=O), all of which can be detected in atherosclerotic plaques. 7-OOH being highly reactive, generates 7-OH and 7=O via free radical redox turnover, so 7-OH/7=O levels typically far exceed those of 7-OOH. To limit adverse buildup of cholesterol and its oxides, macrophages export these lipids to HDL and other acceptors via reverse cholesterol transport (RCT). Several intracellular proteins are involved in RCT, including StarD1, which transports cholesterol into mitochondria (Mito) for conversion to 27-hydroxycholesterol (27-OH) by Cyp27A1 hydroxylase, 27-OH then signaling for ABCA1/G1 transporter expression and cholesterol efflux. Although effects of redox-inactive 7=O/7-OH have been widely studied, little attention has been directed to potentially more dangerous 7-OOH, which can be StarD1-delivered into Mito along with cholesterol, as we recently discovered. We also observed that 7-OOH can stimulate Mito replication (mitogenesis). The significance of 7-OOH trafficking with regard to cardiovascular disease will be discussed. (Supported by NCN grant 2017/26/M/NZ3/01232)