Free radical oxidation of cholesterol and its precursors: Implications in cholesterol biosynthesis disorders

Abstract

Free radical oxidation of cholesterol and its precursors contribute significantly to the pathophysiology of a number of human diseases. This review intends to summarize recent developments and provide a perspective on the reactivities of sterols toward free radical oxidation, the free radical reaction mechanism, and the biological consequences of oxysterols derived from the highly oxidizable cholesterol precursor, 7-dehydrocholesterol. We propose that the rigid structures, additional substituents on the double bonds, and the well-aligned reactive C–H bonds in sterols make them more prone to free radical oxidation than their acyclic analogs found in unsaturated fatty acids. The mechanism of sterol peroxidation follows some well-established reaction pathways found in the free radical peroxidation of polyunsaturated fatty acids, but sterols also undergo some reactions that are unique to these compounds. Peroxidation of 7-dehydrocholesterol gives arguably the most diverse set of oxysterol products that have been observed to date. The metabolism of these oxysterols in cells and the biological consequences of their formation will be discussed in the context of the pathophysiology of the human disease Smith–Lemli–Opitz syndrome. Considering the high reactivity of sterols, we propose that a number of other cholesterol biosynthesis disorders may be associated with oxidative stress.

Keywords::

• peroxidation
• autoxidation
• oxysterol
• 7-dehydrocholesterol
• Smith–Lemli–Opitz syndrome

Acknowledgements

We thank collaborators and colleagues for their contribution and insights on related projects, including Drs. Zeljka Korade (Psychiatry, Vanderbilt), Karoly Mirnics (Psychiatry, Vanderbilt), Steven J. Fliesler (ophthalmology, SUNY-Buffalo), Wei Liu, Katherine Windsor, and Thiago C.Genaro-Mattos.

Declaration of interest

The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.

This work was supported by grants from the National Institute of Health (K99HD073270 (L.X.) and R01HD064727 (N.A.P.)) and National Science Foundation (CHE-1057500 (N.A.P.)). The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.