Estradiol Uses Different Mechanisms in Astrocytes from the Hippocampus of Male and Female Rats to Protect against Damage Induced by Palmitic Acid.

Laura M Frago,Alejandra Freire-Regatillo,Julie A Chowen,Sandra Canelles,Luis M Garcia-Segura,Vicente Barrios,Pilar Argente-Arizón,Jesús Argente

doi:10.3389/fnmol.2017.00330

Abstract

An excess of saturated fatty acids can be toxic for tissues, including the brain, and this has been associated with the progression of neurodegenerative diseases. Since palmitic acid (PA) is a free fatty acid that is abundant in the diet and circulation and can be harmful, we have investigated the effects of this fatty acid on lipotoxicity in hippocampal astrocytes and the mechanism involved. Moreover, as males and females have different susceptibilities to some neurodegenerative diseases, we accessed the responses of astrocytes from both sexes, as well as the possible involvement of estrogens in the protection against fatty acid toxicity. PA increased endoplasmic reticulum stress leading to cell death in astrocytes from both males and females. Estradiol (E2) increased the levels of protective factors, such as Hsp70 and the anti-inflammatory cytokine interleukin-10, in astrocytes from both sexes. In male astrocytes, E2 decreased pJNK, TNFα, and caspase-3 activation. In contrast, in female astrocytes E2 did not affect the activation of JNK or TNFα levels, but decreased apoptotic cell death. Hence, although E2 exerted protective effects against the detrimental effects of PA, the mechanisms involved appear to be different between male and female astrocytes. This sexually dimorphic difference in the protective mechanisms induced by E2 could be involved in the different susceptibilities of males and females to some neurodegenerative processes.

Highlights

Astrocytes are the most abundant cell type in the central nervous system and are essential to maintain its homeostasis
glial fibrillary acidic protein (GFAP) levels were increased in response to 0.25 and 0.5 mM palmitic acid (PA) (P < 0.05; Figure 1A); in females at the two lower doses tested, a decrease in GFAP protein levels was observed (P < 0.01; Figure 1B)
PA had no effect on IL-6 protein levels in female astrocytes (Figure 1D)

Summary

Introduction

Astrocytes are the most abundant cell type in the central nervous system and are essential to maintain its homeostasis. Plasma concentrations of free fatty acids (FFA) are elevated in obese subjects (Arner and Ryden, 2015) and this can induce lipotoxicity, resulting in cell damage and the disruption of cellular homeostasis due to oxidative stress (de Morentin et al, 2010). PA can inhibit the insulin signaling pathway, which induces endoplasmic reticulum stress in hypothalamic neurons (Mayer and Belsham, 2010) This fatty acid up-regulates BACE1 with the consequent amyloidogenic processing of beta-amyloid precursor protein in primary cortical neurons by elevating oxidative stress and FFA metabolism in astrocytes (Patil et al, 2007) and PA-induced lipotoxicity induces apoptotic cell death in some cell types (Maestre et al, 2003; Martins de Lima et al, 2006; Ricchi et al, 2009). PA-induced lipotoxicity has not been extensively studied in astrocytes

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