Tibolone attenuates inflammatory response by palmitic acid and preserves mitochondrial membrane potential in astrocytic cells through estrogen receptor beta

González-Giraldo, Yeimy; Forero, Diego A.; Echeverrı́a, Valentina; García‐Segura, Luis M.; Barreto, George E.

doi:10.1016/j.mce.2019.02.017

Cited by 32 publications

(41 citation statements)

References 92 publications

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“…All the reactions involved in the conversion of extracellular glutamate, glycine, cysteine and glucose to extracellular glutamine, glycine, serine-D, reduced glutathione, lactate, and ATP were added, as they are essential for the normal astrocytic metabolism (Barreto et al, 2011;Souza et al, 2019). Exchange reactions were limited to components of the Dulbecco's Modified Eagle Medium (DMEM) as an input, and the gliotransmitters, glutamine, D-serine, ATP and glutamate, reduced glutathione, lactate, glucose, nitric oxide, prostaglandins and leukotrienes as output, in accordance with previous experimental studies from our group (Avila-Rodriguez et al, 2016;Cabezas et al, 2018;González-Giraldo et al, 2019). Finally, we developed the R Package "MinVal" to validate the syntax of the model, the mass-charge and the creation of SBML files (Osorio et al, 2017).…”

Section: Tissue Specific Model Constructionsupporting

confidence: 59%

“…Uptake values where each objective function reached IC 50 was selected and subsequently averaged. Moreover, the modeled inhibitory effects are in congruence with the reported damaging effects of palmitate in astrocytes (Gupta et al, 2012;González-Giraldo et al, 2019). Finally, a "Tibolone treatment under inflammation" scenario was defined as an "inflammatory scenario" which included 279 additional reactions associated with the metabolic effects exerted by estradiol and derivates compounds obtained in KEGG (Kanehisa et al, 2014), and ten specific reactions associated with tibolone metabolism (Kloosterboer, 2004) not included in RECON 2.04, which are described in Table 2.…”

Section: Metabolic Scenariosmentioning

confidence: 99%

“…Different works have shown that astrocytes are key mediators in the brain lipid homeostasis and B-oxidation of fatty acid (Panov et al, 2014). Interestingly, saturated free fatty acids, including stearic acid, lauric acid, and palmitic acid, are closely associated with neurodegenerative processes such as traumatic brain injury (TmBI), dementia, stroke, epilepsy, spinal cord injury, Parkinson's disease (PD) reactive gliosis, neuroinflammation, and Alzheimer's disease (AD) (Bruce-Keller et al, 2001White et al, 2009;Gupta et al, 2012;Little et al, 2012;González-Giraldo et al, 2019). Additionally, both palmitic acid and stearic acid were shown to increase the secretion of Aβ amyloid peptide in an AD cellular model (Amtul et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…In this aspect, tibolone is a synthetic steroid (Kloosterboer, 2001), with estrogenic, progestogenic, and weak androgenic actions (González-Giraldo et al, 2019). It has been used for the treatment of climacteric symptoms and osteoporosis in postmenopausal women (Rymer et al, 1994;Rymer, 1998) and has also shown beneficial antidepressant effects in menopausal women (Kulkarni et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown that tibolone exerts its neuroprotective effects through the activation of the Akt/GSK3ß signaling pathway which in turns causes the reduction of Tau phosphorylation in the hippocampus and cerebellum of ovariectomized rats, the increase in antioxidant activity in primary neuronal cultures and the increase in the expression of the antiapoptotic protein Bcl-2 (Genazzani et al, 2006;Belenichev et al, 2012;Pinto-Almazán et al, 2012;Avila-Rodriguez et al, 2014). Nevertheless, there is little information regarding the effects of tibolone in astrocytes or the metabolic pathways related with its neuroprotective mechanisms (Avila-Rodriguez et al, 2014;González-Giraldo et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Multiple Pathways Involved in Palmitic Acid-Induced Toxicity: A System Biology Approach

et al. 2020

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Inflammation is a complex biological response to injuries, metabolic disorders or infections. In the brain, astrocytes play an important role in the inflammatory processes during neurodegenerative diseases. Recent studies have shown that the increase of free saturated fatty acids such as palmitic acid produces a metabolic inflammatory response in astrocytes generally associated with damaging mechanisms such as oxidative stress, endoplasmic reticulum stress, and autophagic defects. In this aspect, the synthetic neurosteroid tibolone has shown to exert protective functions against inflammation in neuronal experimental models without the tumorigenic effects exerted by sexual hormones such as estradiol and progesterone. However, there is little information regarding the specific mechanisms of tibolone in astrocytes during inflammatory insults. In the present study, we performed a genome-scale metabolic reconstruction of astrocytes that was used to study astrocytic response during an inflammatory insult by palmitate through Flux Balance Analysis methods and data mining. In this aspect, we assessed the metabolic fluxes of human astrocytes under three different scenarios: healthy (normal conditions), induced inflammation by palmitate, and tibolone treatment under palmitate inflammation. Our results suggest that tibolone reduces the L-glutamate-mediated neurotoxicity in astrocytes through the modulation of several metabolic pathways involved in glutamate uptake. We also identified a set of reactions associated with the protective effects of tibolone, including the upregulation of taurine metabolism, gluconeogenesis, cPPAR and the modulation of calcium signaling pathways. In conclusion, the different scenarios studied in our model allowed us to identify several metabolic fluxes perturbed under an inflammatory response and the protective mechanisms exerted by tibolone.

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Section: Tissue Specific Model Constructionsupporting

confidence: 59%

Section: Metabolic Scenariosmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multiple Pathways Involved in Palmitic Acid-Induced Toxicity: A System Biology Approach

et al. 2020

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

et al. 2023

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Chronic intake of a high-fat diet increases saturated fatty acids in the brain causing the progression of neurodegenerative diseases. Palmitic acid is a free fatty acid abundant in the diet that at high concentrations may penetrate the blood–brain barrier and stimulate the production of pro-inflammatory cytokines, leading to inflammation in astrocytes. The use of the synthetic neurosteroid tibolone in protection against fatty acid toxicity is emerging, but its transcriptional effects on palmitic acid–induced lipotoxicity remain unclear. Herein, we performed a transcriptome profiling of normal human astrocytes to investigate the molecular mechanisms by which palmitic acid causes cellular damage to astrocytes, and whether tibolone could reverse its detrimental effects. Astrocytes undergo a profound transcriptional change at 2 mM palmitic acid, affecting the expression of 739 genes, 366 upregulated and 373 downregulated. However, tibolone at 10 nM does not entirely reverse palmitic acid effects. Additionally, the protein–protein interaction reveals two novel gene clustering modules. The first module involves astrocyte defense responses by upregulation of pathways associated with antiviral innate immunity, and the second is linked to lipid metabolism. Our data suggest that activation of viral response signaling pathways might be so far, the initial molecular mechanism of astrocytes in response to a lipotoxic insult by palmitic acid, triggered particularly upon increased expression levels of IFIT2, IRF1, and XAF1. Therefore, this novel approach using a global gene expression analysis may shed light on the pleiotropic effects of palmitic acid on astrocytes, and provide a basis for future studies addressed to elucidate these responses in neurodegenerative conditions, which is highly valuable for the design of therapeutic strategies.

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Tibolone Ameliorates the Lipotoxic Effect of Palmitic Acid in Normal Human Astrocytes

et al. 2020

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Tibolone attenuates inflammatory response by palmitic acid and preserves mitochondrial membrane potential in astrocytic cells through estrogen receptor beta

Cited by 32 publications

References 92 publications

Multiple Pathways Involved in Palmitic Acid-Induced Toxicity: A System Biology Approach

Multiple Pathways Involved in Palmitic Acid-Induced Toxicity: A System Biology Approach

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

Tibolone Ameliorates the Lipotoxic Effect of Palmitic Acid in Normal Human Astrocytes

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