Abstract
Obesity and metabolic syndrome are associated with cognitive decline and dementia. Palmitic acid (PA) is increased in the cerebrospinal fluid of obese patients with cognitive impairment. This study was therefore designed to examine fatty acid (FA) lipotoxicity in BV2 microglia cells. We found that PA induced time- and dose-dependent decrease in cell viability and increase in cell death without affecting the cell cycle profile and that PA lipotoxicity did not depend on cell surface free fatty acid receptors but rather on FA uptake. Treatment with sulfosuccinimidyl oleate (SSO), an irreversible inhibitor of fatty acid translocase CD36, significantly inhibited FA uptake in BSA- and PA-treated cells and blocked PA-induced decrease in cell viability. Inhibition of ER stress or treatment with N-acetylcysteine was not able to rescue PA lipotoxicity. Our study also showed that unsaturated fatty acids (UFAs), such as linoleic acid (LA), oleic acid (OA), α-linolenic acid (ALA), and docosahexaenoic acid (DHA), were not lipotoxic but instead protected microglia against PA-induced decrease in cell viability. Co-treatment of PA with LA, OA, and DHA significantly inhibited FA uptake in PA-treated cells. All UFAs tested induced the incorporation of FAs into and the amount of neutral lipids, while PA did not significantly affect the amount of neutral lipids compared with BSA control.
Highlights
IntroductionFree fatty acids (FFAs) are central to many critical cellular functions serving as cellular energy substrates, participating in cell signaling as receptor ligands and second messengers, and contributing to the structural integrity of cells as integrants of cellular membranes [1]
We found that both FFAR1 and FFAR4 were expressed in BV2 microglia cells, but FFAR1 mRNA was significantly lower than FFAR4 mRNA (Figure 3A)
Lipotoxicity refers to cellular toxicity caused by excess Free fatty acids (FFAs) [41]
Summary
Free fatty acids (FFAs) are central to many critical cellular functions serving as cellular energy substrates, participating in cell signaling as receptor ligands and second messengers, and contributing to the structural integrity of cells as integrants of cellular membranes [1]. The level of palmitic acid (PA), a principal FFA constituent of human plasma [4] and a key SFA in membrane phospholipids [5], is elevated in the cerebrospinal fluid of overweight and obese subjects and this elevation is associated with decreased cognitive performance [6]. SFA-induced functional abnormalities in neuronal and glial cells have been suggested to contribute to cognitive decline and neurodegenerative conditions [7], while UFA-containing fish oil supplementation decreases apoptosis in hippocampus and cerebrum of rodents [8,9]
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