Oxysterols: implication in biological processes and diseases

Abstract

Cholesterol is ubiquitous and necessary for the biosynthesis of steroidal hormones, bile salts and to maintain the stability of biological membranes in animal cells. Its regulation and homeostasis is ensured by the conjugated action of specific factors/enzymes/receptors such as SREBP, HMG-CoA or LXR. LDL and HDL are responsible to transport cholesterol and provide the cells to build and maintain the membranes, etc. Cholesterol, as lipids in general, is susceptible to oxidation and some positions in the chemical structure are more prone to oxidative attack; the most common cholesterol derivatives produced by oxidative attack are hydroxyl derivatives, keto derivatives, hydroperoxydes, epoxides and carboxyl derivatives. Those oxidized cholesterol derivatives are called Oxysterols or Cholesterol Oxides. Cholesterol oxidation occurs by autoxidation processes in dietary food exposed to heating treatments in the presence of oxygen or have been stored for long periods and exposed to sunlight and oxygen. This autoxidation process constitutes an exogenous source of oxysterols i.e. they can be ingested from the diet. On the other hand, cholesterol oxidation can be mediated by enzymes belonging to the family of cytochrome P450 of oxygenases and autoxidation processes are also possible inside the body constituting both the endogenous source of oxysterols. Oxysterols are characterized by a diverse profile of biological activities, including effects on sphingolipid metabolism, platelet aggregation, apoptosis, cytotoxicity, binding to specific transporters, relation with the Hedgehog pathway, binding to the oestrogen receptor and protein prenylation. The most notable oxysterol activity is related to the regulation of cholesterol homeostasis, which appears to be controlled in part by a complex series of interactions of oxysterols 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. Oxysterols are suspected to be involved in cholesterol homeostasis but also seem to play a role or at least are involved in the progression of neurodegenerative diseases and in carcinogenesis especially due to their interaction with cell death mechanisms (apoptosis) and because of their relationship with inflammatory processes. Because of their relevant biological properties and their implication in important systemic processes and in the etiology or pathophysiology of certain diseases, this work provides clarifications on the role of Oxysterols in cholesterol homeostasis and provides insights on their direct or indirect role in the pathophysiology of Alzheimer’s disease and Cancer as well as if these could represent a direct or indirect target for therapeutic action. The bibliographical investigation led to conclude that, currently, it is known that oxysterols are not the sole regulators of cholesterol homeostasis, although they are significant players in the regulation of this process. On the other hand, it has been demonstrated that they are involved in processes related to the onset and/or progression of neurodegenerative diseases such as Alzheimer, and with carcinogenesis. Because of this, Oxysterols could represent a big revolution in the field of biomedicine as potential direct or indirect targets for therapeutic action, but there is still the need of more in vivo experiments to translate their activities in humans and before deciding which strategy is applicable to develop a potential disease treatment