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

Abstract

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.

Tibolone Improves Locomotor Function in a Rat Model of Spinal Cord Injury by Modulating Apoptosis and Autophagy

“…In addition, TIB restored the expression of some proteins related to transport, translation and apoptosis. Also, TIB increased proteins related to cell survival processes [82] and reduced gliosis and neuronal loss in the cerebral cortex after acute brain injury [42]. These findings suggest that TIB is a promising neuroactive steroid for reducing apoptosis.…”

Machine learning encodes urine and serum metabolic patterns for autoimmune disease discrimination, classification and metabolic dysregulation analysis

“…[43][44][45][46][47][48][49][50][51] Perturbation of the biosynthesis of unsaturated fatty acids, fatty acid elongation, fatty acid degradation, fatty acid biosynthesis, glycerolipid metabolism, fatty acid elongation in mitochondria, fatty acid metabolism, steroid biosynthesis and bile acid biosynthesis were caused by the up-regulation of palmitic acid in disease groups, and the down-regulation of 3-oxodecanoic acid also affected fatty acid biosynthesis. [52][53][54][55][56][57][58][59] Other perturbed lipid-related metabolic pathways, including glycerophospholipid metabolism and the mitochondrial beta-oxidation of short-chain saturated fatty acids, were related to the down-regulation of phosphatidylcholine (PC) and octanoylcarnitine, respectively. 39,55 These regulations were critical for the homeostasis of cellular membranes and lipid stores.…”

Palmitic Acid Upregulates Type I Interferon–Mediated Antiviral Response and Cholesterol Biosynthesis in Human Astrocytes

“…On the other hand, conversely to previous reports [ 18 ], our findings showed that TIB did not reverse the transcriptional changes induced by PA in astrocytes during the experimental conditions, despite its protective effect at the cellular level. However, the proteomic analysis identified that TIB altered the expression of proteins associated with the endoplasmic reticulum exit site and cadherin binding in comparison with PA [ 20 ]. These different results of TIB in a lipotoxic astrocytes scenario are probably due to variability in the expression pattern of estrogen receptors (ERs) [ 65 , 66 ], or because the molecular responses after ER activation can be time-dependent [ 67 ].…”

“…Although some genes have been explored in astrocytic cell models submitted to PA and TIB stimuli [ 15 ], to the best of our knowledge, there is no evidence of studies analyzing transcriptome-wide expression under these conditions. Regarding downstream molecules, such as proteins and metabolites, two recent studies have investigated the effects of PA and TIB treatments in in vitro experiments of astrocytes [ 19 , 20 ].…”