Oxysterols: Modulators of Cholesterol Metabolism and Other Processes

Abstract

Oxygenated derivatives of cholesterol (oxysterols) present a remarkably diverse profile of biological activities, including effects on sphingolipid metabolism, platelet aggregation, apoptosis, and protein prenylation. The most notable oxysterol activities center around the regulation of cholesterol homeostasis, which appears to be controlled in part by a complex series of interactions of oxysterol ligands with various receptors, such as the oxysterol binding protein, the cellular nucleic acid binding protein, the sterol regulatory element binding protein, the LXR nuclear orphan receptors, and the low-density lipoprotein receptor. Identification of the endogenous oxysterol ligands and elucidation of their enzymatic origins are topics of active investigation. Except for 24, 25-epoxysterols, most oxysterols arise from cholesterol by autoxidation or by specific microsomal or mitochondrial oxidations, usually involving cytochrome P-450 species. Oxysterols are variously metabolized to esters, bile acids, steroid hormones, cholesterol, or other sterols through pathways that may differ according to the type of cell and mode of experimentation (in vitro, in vivo, cell culture). Reliable measurements of oxysterol levels and activities are hampered by low physiological concentrations (approximately 0.01-0.1 microM plasma) relative to cholesterol (approximately 5,000 microM) and by the susceptibility of cholesterol to autoxidation, which produces artifactual oxysterols that may also have potent activities. Reports describing the occurrence and levels of oxysterols in plasma, low-density lipoproteins, various tissues, and food products include many unrealistic data resulting from inattention to autoxidation and to limitations of the analytical methodology. Because of the widespread lack of appreciation for the technical difficulties involved in oxysterol research, a rigorous evaluation of the chromatographic and spectroscopic methods used in the isolation, characterization, and quantitation of oxysterols has been included. This review comprises a detailed and critical assessment of current knowledge regarding the formation, occurrence, metabolism, regulatory properties, and other activities of oxysterols in mammalian systems.

Light-induced exacerbation of retinal degeneration in a rat model of Smith–Lemli–Opitz syndrome

“…Hence, it is reasonable to suspect that the in situ formation of 7DHC in a highly oxidizing environment would result in the progressive conversion of at least some of the 7DHC to oxysterols, which would then compromise cellular functions and viability, ultimately resulting in the observed retinal degeneration. It is known that the levels of oxysterol required to induce various pathological sequellae are extremely small, compared to the steady-state levels of the parent sterol (Schroepfer, 2000;Panini and Sinensky, 2001;Chang and Phelan, 2002). Since such oxysterol formation is potentiated by light exposure, one might think that this would explain the observed exacerbation of retinal damage in the SLOS rat model by intense light.…”

“…A hallmark of SLOS is the abnormal and excessive accumulation of 7-dehydrocholesterol (7DHC), an immediate precursor of cholesterol (Tint et al, 1994). 7DHC is extremely labile to oxidation (Girotti, 2002), far more so than is cholesterol, and oxysterols are highly toxic to cells (Chang and Phelan, 2002;Panini and Sinensky, 2001;Schroepfer, 2000;Gaoua et al, 1999).…”

Different apoptotic mechanisms are involved in the antiproliferative effects of 7β-hydroxysitosterol and 7β-hydroxycholesterol in human colon cancer cells

“…24,[31][32][33] They may also exert their effects by lowering cholesterol availability for cell membrane formation by inhibiting 3-hydroxy-methylglutaryl coenzyme A reductase (HMG-CoA reductase), a key enzyme in cholesterol synthesis. 34 Cholesterol oxides bind to specific membrane receptors or cytosolic binding proteins, leading to the perturbation of cholesterol synthesis. [35][36][37] It was also shown that 7b-hydroxycholesterol (7b-OHchol) and 7-ketocholesterol may initiate nonapoptotic death in U937 cells.…”

“…Cytotoxicity of 7b-OHchol or other cholesterol oxides have been reported on HT-29 and SW620 human colon cancer cells. 39 Since 7b-OHsito and 7b-OHchol are the most abundant hydroxysterols 34,40 present in food after cooking and storage, it was of interest to compare their cytotoxic effects. In order to determine whether both molecules induced the same or different apoptotic process in cancer cells, we assessed cell viability, cell cycle analysis, caspases activities and DNA fragmentation.…”

Structure‐apoptotic potency evaluations of novel sterols using human leukemic cells

“…The relatively greater sensitivity of certain malignant, as opposed to normal, cells offers an opportunity to use oxysterols as chemotherapeutic drugs. A few investigators have recognized their potential as therapeutic agents (15)(16)(17)(18).…”