Oxysterols and their cellular effectors

Abstract

Oxysterols are oxidized 27-carbon cholesterol derivatives or by-products of cholesterol biosynthesis, with a spectrum of biologic activities. Several oxysterols have cytotoxic and pro-apoptotic activities, the ability to interfere with the lateral domain organization, and packing of membrane lipids. These properties may account for their suggested roles in the pathology of diseases such as atherosclerosis, age-onset macular degeneration and Alzheimer's disease. Oxysterols also have the capacity to induce inflammatory responses and play roles in cell differentiation processes. The functions of oxysterols as intermediates in the synthesis of bile acids and steroid hormones, and as readily transportable forms of sterol, are well established. Furthermore, their actions as endogenous regulators of gene expression in lipid metabolism via liver X receptors and the Insig (insulin-induced gene) proteins have been investigated in detail. The cytoplasmic oxysterol-binding protein (OSBP) homologues form a group of oxysterol/cholesterol sensors that has recently attracted a lot of attention. However, their mode of action is, as yet, poorly understood. Retinoic acid receptor-related orphan receptors (ROR) α and γ, and Epstein-Barr virus induced gene 2 (EBI2) have been identified as novel oxysterol receptors, revealing new physiologic oxysterol effector mechanisms in development, metabolism, and immunity, and evoking enhanced interest in these compounds in the field of biomedicine.

Figure 1

Structure and origin of selected common oxysterols. Most of the oxysterol species displayed are generated by enzymes that belong to the cytochrome P450 family (CYP). CH25H, cholesterol 25-hydroxylase, is a di-iron enzyme. The enzymatically derived species are indicated with green, products of cholesterol autoxidation with red, and a species derived from a shunt of the cholesterol biosynthetic process with blue print (Modified from [2] with kind permission from Springer Science+Business Media B.V.).

Figure 2

A schematic presentation summarizing the major functions of oxysterols. ROR, retinoic acid receptor-related orphan receptor; OSBP, oxysterol-binding protein; ORP, OSBP-related protein; LXR, liver X receptor; SREBP, sterol regulatory element binding protein; Insig, insulin-induced gene; ROS, reactive oxygen species; Bcl-2, B-cell lymphoma 2; IgA, immunoglobulin A; CNS, central nervous system.