Lipid Reshaping and Lipophagy Are Induced in a Modeled Ischemia-Reperfusion Injury of Blood Brain Barrier

Abstract

Ischemic-reperfusion (I/R) injury induced a remodeling of protein and lipid homeostasis, under oxidative stress and inflammatory status. Starvation occurring during I/R is a condition leading to autophagy activation, which allows abnormal material clearance or amino acid, or both, and fatty acid (FA) recycling essential for survival. This study investigated the lipid reshaping, peroxidation, and related-signaling pathways, in rat brain endothelial cells (RBE4) subjected to 3 h of oxygen and glucose deprivation (OGD) and restoration of standard condition (I/R in vitro model). Lipids and proteins were analyzed after 1 or 24 h of oxygen and nutrient restoration. Together with the oxidative stress and inflammatory status, I/R injury induced a reshaping of neutral lipids and biogenesis of lipid droplets (LD) with excessive lipid storage. The increase of LC3-II/LC3-I ratio, an autophagy marker, and LC3 co-localization with LD suggest the activation of lipophagy machinery to counteract the cell engulfment. Lipophagy leads to cholesterol ester (CE) hydrolysis, increasing free cholesterol (FC) secretion, which occurred by specific transporters or unconventional exocytosis pathways, or both. Here, we propose that an unconventional spreading of FC and other lipid metabolites may influence the neurovascular unit (NVU) cells, contributing to Blood brain barrier (BBB) alteration or adaptation, or both, to the cumulative effects of several transient ischemia.

Lipidomic signature of stroke recurrence after transient ischemic attack

“…However, more studies are needed to validate this concept, as well as the biological relevance of this particular lipid species instead of other plasmalogens. Importantly, these findings are in line with previous observations in animal models of ischemia-reperfusion 17 , 24 and in ischemic stroke patients 25 , suggesting that this lipid set express a condition of impaired stress in SR patients compared to TIA non-SR patients.…”

Coffee-Derived Phenolic Compounds Activate Nrf2 Antioxidant Pathway in I/R Injury In Vitro Model: A Nutritional Approach Preventing Age Related-Damages

“…During OGD, the cells enter energy deficiency, and thus phosphorylation processes are inhibited. Moreover, ischemic conditions inhibit the usual cell energetic metabolisms and promote the autophagy pathway to recycle cellular components and damaged organelles for self-sustaining [ 43 , 44 ]. In the first hour of reperfusion, however, the kinase phosphorylation state significantly increased (163% Akt; 50% and 62% for p42 and p44 respectively), probably due to the restored availability of energy sources ( Figure 5 ).…”

Selective autophagy as a therapeutic target for neurological diseases

“…Therefore, selective degradation of these types of superfluous and harmful lipids, namely lipophagy, can substantially reduce the brain injuries after stroke. Indeed, ischemic stroke reportedly induced the activation of lipophagy that occurred to effectively remove the lipid excess, modulate the lipid homeostasis, and counteract the intracellular TG overload [ 282 ]. However, induced excessive lipophagy can be a doubled-edged sword, because some products of LDs, such as ceramides and PUFA-derived lipid mediators, are detrimental to the adjacent cells [ 283 ].…”