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.
Highlights
Oxysterols are 27-carbon oxidized derivatives of cholesterol or by-products of the cholesterol biosynthetic process with multiple biological activities
24(S)-OHC originates from neurons in the central nervous system, the sterol homeostasis of which depends on the synthesis of this oxysterol catalyzed by the cholesterol hydroxylase CYP46A1 [6], 7α- and 27-OHC are synthesized by the liver by CYP7A1 and CYP27A1 as the first intermediates of classic and acidic bile acid synthetic pathways, respectively [7]; CYP27A1 is functional in non-hepatic cells [8]. 4β-OHC is generated by the hepatic drug metabolizing enzyme CYP3A4, which is markedly induced by certain anti-epileptic pharmaceuticals [9]
The authors discovered that liver X receptor (LXR) target genes are induced in RORα-knock out mice and vice versa, suggesting a mutually suppressive function of these nuclear receptors. These findings indicate that RORα and RORγ serve as novel sensors for oxysterols and display an overlapping ligand preference and functional cross-talk with the LXR, suggesting the presence of an intriguingly complex sterol-controlled network of gene regulatory actions related with metabolic disease and atherosclerosis
Summary
Oxysterols are 27-carbon oxidized derivatives of cholesterol or by-products of the cholesterol biosynthetic process with multiple biological activities. The physiologically most important oxysterols are generated in cells by mitochondrial or endoplasmic reticulum cholesterol hydroxylases belonging to the cytochrome P450 family [4,5]. Of these species, the most abundant in human serum are 27-, 24(S)-, 7α-, and 4β-hydroxycholesterol (OHC). The most abundant oxysterols generated through autoxidation are modified at the 7-position of the cholesterol B-ring. Oxysterols are present in mammalian tissues at very low concentrations, as mixtures accompanied by a high excess of cholesterol They are found enriched in pathologic structures such as macrophage foam cells, atherosclerotic lesions, cataracts, and gall stones. The present review focuses on the newly identified receptors and cellular effector pathways of oxysterols
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