Tibolone Pre‐Treatment Ameliorates the Dysregulation of Protein Translation and Transport Generated by Palmitic Acid‐Induced Lipotoxicity in Human Astrocytes: A Label‐Free MS‐Based Proteomics and Network Analysis

Excessive accumulation and release of fatty acids (FAs) in adipose and non‐adipose tissue are characteristic of obesity and are associated with the leading causes of death worldwide. Chronic exposure to high concentrations of FAs such as palmitic acid (pal) is a risk factor for developing different neurodegenerative diseases (NDs) through several mechanisms. In the brain, astrocytic dysregulation plays an essential role in detrimental processes like metabolic inflammatory state, oxidative stress, endoplasmic reticulum stress, and autophagy impairment. Evidence shows that tibolone, a synthetic steroid, induces neuroprotective effects, but its molecular mechanisms upon exposure to pal remain largely unknown. Due to the capacity of identifying changes in the whole data‐set of proteins and their interaction allowing a deeper understanding, we used a proteomic approach on normal human astrocytes under supraphysiological levels of pal as a model to induce cytotoxicity, finding changes of expression in proteins related to translation, transport, autophagy, and apoptosis. Additionally, tibolone pre‐treatment showed protective effects by restoring those same pal‐altered processes and increasing the expression of proteins from cell survival processes. Interestingly, ARF3 and IPO7 were identified as relevant proteins, presenting a high weight in the protein‐protein interaction network and significant differences in expression levels. These proteins are related to transport and translation processes, and their expression was restored by tibolone. This work suggests that the damage caused by pal in astrocytes simultaneously involves different mechanisms that the tibolone can partially revert, making tibolone interesting for further research to understand how to modulate these damages.