Electrophilic oxysterols: generation, measurement and protein modification

Abstract

Cholesterol is an essential component of mammalian plasma membranes. Alterations in sterol metabolism or oxidation have been linked to various pathological conditions, including cardiovascular diseases, cancer, and neurodegenerative disorders. Unsaturated sterols are vulnerable to oxidation induced by singlet oxygen and other reactive oxygen species. This process yields reactive sterol oxidation products, including hydroperoxides, epoxides as well as aldehydes. These oxysterols, in particular those with high electrophilicity, can modify nucleophilic sites in biomolecules and affect many cellular functions. Here, we review the generation and measurement of reactive sterol oxidation products with emphasis on cholesterol hydroperoxides and aldehyde derivatives (electrophilic oxysterols) and their effects on protein modifications.

Graphical Abstract

Keywords:

• Cholesterol
• oxysterol
• electrophiles
• oxidative stress
• protein modification

Disclosure statement

No potential conflict of interest was reported by the author(s).

Table 4. Proteins modified by secosterol aldehydes, indicating biological samples where aldehydes were detected, and the method used for their characterization.

Notes

1 Values from (110]. ChOOH, which is more polar than cholesterol, can migrate to other cellular compartments. In fact, Girotti’s group presented several evidences showing dissemination/translocation of ChOOH species between membranes [8,174–176]. Using models comprised by photoperoxidized erythrocyte ghosts as donor membranes and unilamellar liposomes as acceptors, they observed a one order of magnitude faster translocation rates for ChOOH than for cholesterol itself [176]. Additionally, studies using recombinant proteins and cells demonstrated that ChOOH translocation to intracellular compartments can be accelerated by lipid transfer proteins, such as the sterol carrier protein 2 (SCP-2) [177] and steroidogenic acute regulatory proteins (StARD1 and StARD4) [178]. SCP-2, a 13.2 kDa protein, has broad substate specificity, and is able to catalyze the translocation of sterols or phospholipids. In contrast, StAR proteins are known to specifically bind steroidal molecules. For example, StARD4 is known to facilitate cholesterol transport to the endoplasmic reticulum for storage as cholesteryl esters or to mitochondria for 27-OHC and bile acid production [179–181]. Notably, StaRD1 and StARD4 showed enhanced ChOOH uptake and transfer to mitochondria in stimulated macrophages resulting in.

Additional information

Funding

Authors are members of the CEPID-Redoxoma supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Grant 2013/07937-8. S.M. was also supported by FAPESP Grant 10/50891-0, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Grant 424094/2016-9 and 309083/2017-6, NAP-Redoxoma, Pró-Reitoria de Pesquisa USP, and CAPES. A.I is a recipient of a FAPESP scholarship Grant 2017/13804-1.