Lipid peroxidation plays important roles in the pathophysiology of common human diseases such as atherosclerosis, diabetes, Alzheimer's, Parkinson's disease, etc. In our study on free radical-mediated lipid peroxidation (autoxidation) reactions, 7-dehydrocholesterol (7-DHC), the immediate biosynthetic precursor to cholesterol, was found to be the most reactive lipid molecule known to date toward free radical oxidation. It is oxidized ca. 200 times faster than is cholesterol, and more than 10 times faster than arachidonic acid. Autoxidation of 7-DHC in solution leads to over a dozen oxidation products (i.e., oxysterols) via a complex reaction mechanism, and these oxysterols exert a variety of biological activities, including cytotoxicity and induction of gene expression changes in cells.7-DHC is accumulated in individuals affected with Smith-Lemli-Opitz syndrome (SLOS), a metabolic disorder that is caused by mutations in the gene encoding 7-DHC reductase. A number of novel 7-DHC-derived oxysterols were recently identified in cell and animal models for SLOS. Metabolic studies suggested that some of these oxysterols were originated from free radical oxidation, while others were formed via enzymatic oxidation catalyzed by cytochrome P450. Significantly, antioxidant supplementation was found to suppress the formation of the non-enzymatically-formed oxysterols in fibroblasts from SLOS patients. My current research  focus on establishing metabolic signatures of SLOS cells and tissues using advanced mass spectrometry, elucidating the biological actions of the endogenously formed 7-DHC-derived oxysterols, and developing therapeutic approaches through the inhibition of the formation of these oxysterols in animal models of SLOS. The outcome of these lines of research is expected to shed light on other human diseases that are associated with elevated levels of 7-DHC, such as cerebrotendinous xanthomatosis, breast cancer, skin diseases, etc.

Free radical oxidation of 7-dehydrocholesterol and its role in human diseases

246th National Meeting (2013)

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