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Lipotoxic Effects of Palmitic Acid on Astrocytes Are Associated with Autophagy Impairment

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Abstract

Obesity is associated with an increase in the brain levels of saturated free fatty acids, such as palmitic acid (PA). Previous studies have shown that PA exerts proinflammatory actions and reduces cell viability in astrocyte cultures. In this study, we have assessed whether an alteration in autophagy is involved in the effects of PA on astrocytes. Primary astrocytes were obtained from the cerebral cortex of male and female CD1 mouse pups and were incubated for 4.5 or 24 h with 250–500 μM PA. PA increased the levels of LC3-II, an autophagosome marker, and reduced LC3-II flux in astrocytes, suggesting a blockade of autophagy. This effect was observed both after 4.5 and 24 h of treatment with PA. PA had additional effects after treatment for 24 h, increasing the expression of proinflammatory cytokines, decreasing cell viability, and increasing the levels of an endoplasmic reticulum stress marker. In addition, PA decreased the expression of estrogen receptors, but only in female astrocytes. However, the treatment with estradiol, estrogen receptor agonists, or inhibitor of estradiol synthesis did not counteract the action of PA on cell viability. Rapamycin, an autophagy inducer, was unable to prevent the effect of PA on cell viability. In addition, hydroxychloroquine, an autophagy blocker, did not cause per se astrocyte death. These findings suggest that the effect of PA on autophagy is not sufficient to induce astrocyte loss, which is only observed when prolonged PA treatment causes other alterations in astrocytes, such as increased inflammation and endoplasmic reticulum stress.

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Acknowledgements

We thank Elisa Baides Rosell and Nieves Lopez Andradas for excellent technical assistance.

Funding

This work was supported by grants from Ministerio de Economía, Industria y Competitividad (MINECO), Spain (grant numbers BFU2014–51836-C2-1-R and BFU2017-82754-R); Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain; and Fondos FEDER.

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  1. Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

    Ana Ortiz-Rodriguez, Estefania Acaz-Fonseca, Maria Angeles Arevalo & Luis M. Garcia-Segura

  2. Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain

    Estefania Acaz-Fonseca, Maria Angeles Arevalo & Luis M. Garcia-Segura

  3. Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

    Patricia Boya

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Correspondence to Maria Angeles Arevalo.

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All the procedures involving animals used in this study followed the European Commission guidelines (2010/63/UE) and Spanish regulation (RD 53/2013) on the protection of animals for experimental use. These procedures were approved by our institutional animal care and use committee (Comité de Ética de Experimentación Animal del Instituto Cajal) and the Consejería del Medio Ambiente y Territorio (Comunidad de Madrid, PROEX 200/14).

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Ortiz-Rodriguez, A., Acaz-Fonseca, E., Boya, P. et al. Lipotoxic Effects of Palmitic Acid on Astrocytes Are Associated with Autophagy Impairment. Mol Neurobiol 56, 1665–1680 (2019). https://doi.org/10.1007/s12035-018-1183-9

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