Palmitic acid-induced lipotoxicity and protection by (+)-catechin in rat cortical astrocytes

Wong, Kar‐Lok; Wu, Yu Ru; Cheng, Ka Shun; Chan, Paul; Cheung, Chi Wai; Lu, Dah Yuu; Liu, Zhong Min; Leung, Yuk‐Man

doi:10.1016/j.pharep.2014.07.009

Cited by 42 publications

(21 citation statements)

References 26 publications

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“…The neurotrophic effect of OA involved the binding to its receptor peroxisome proliferator-activated receptor-α (Bento-Abreu et al, 2007) The same cytotoxic effect was also observed in the astrocytic cell line, T98G. This PA-induced cytotoxicity was also reported previously in primary cultured mouse astrocytes (Wang et al, 2012) and rat cortical astrocytes (Wong et al, 2014). Wang et al (2012) showed that PA-induced apoptosis in primary mouse astrocytes involved the rise in Bax/Bcl-2 ratio and caspase-3 activation.…”

Section: Discussionsupporting

confidence: 71%

Peer Review #2 of "Palmitic acid induces neurotoxicity and gliatoxicity in SH-SY5Y human neuroblastoma and T98G human glioblastoma cells (v0.1)"

2018

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Background. Obesity-related central nervous system (CNS) pathologies like neuroinflammation and reactive gliosis are associated with high-fat diet (HFD) related elevation of saturated fatty acids like palmitic acid (PA) in neurons and astrocytes of the brain. Methods. Human neuroblastoma cells SH-SY5Y (as a neuronal model) and human glioblastoma cells T98G (as an astrocytic model), were treated with 100-500 µM PA, oleic acid (OA) or lauric acid (LA) for 24 h or 48 h, and their cell viability was assessed by 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of stable overexpression of γ-synuclein (γ-syn), a neuronal protein recently recognized as a novel regulator of lipid handling in adipocytes, and transient overexpression of Parkinson's disease (PD) α-synuclein [α-syn; wild-type (wt) and its pathogenic mutants A53T, A30P and E46K] in SH-SY5Y and T98G cells, were also evaluated. The effects of co-treatment of PA with paraquat (PQ), a Parkinsonian pesticide, and leptin, a hormone involved in the brain-adipose axis, were also assessed. Cell death mode and cell cycle were analyzed by Annexin V/PI flow cytometry. Reactive oxygen species (ROS) level was determined using 2',7'-dichlorofluorescien diacetate (DCFH-DA) assay and lipid peroxidation level was determined using thiobarbituric acid reactive substances (TBARS) assay. Results. MTT assay revealed dose-and time-dependent PA cytotoxicity on SH-SY5Y and T98G cells, but not OA and LA. The cytotoxicity was significantly lower in SH-SY5Y-γ-syn cells, while transient overexpression of wt α-syn or its PD mutants (A30P and E46K, but not A53T) modestly (but still significantly) rescued the cytotoxicity of PA in SH-SY5Y and T98G cells. Co-treatment of increasing concentrations of PQ exacerbated PA's neurotoxicity. Pre-treatment of leptin, an anti-apoptotic adipokine, did not successfully rescue SH-SY5Y cells from PA-induced cytotoxicity-suggesting a mechanism of PAinduced leptin resistance. Annexin V/PI flow cytometry analysis revealed PA-induced increase in percentages of cells in annexin V-positive/PI-negative quadrant (early apoptosis) and subG 0-G 1 fraction, accompanied by a decrease in G 2-M phase cells. The PA-induced ROS production and lipid peroxidation was at greater extent in T98G as compared to that in SH-SY5Y. Discussion. In conclusion, PA induces apoptosis by increasing oxidative stress in neurons and astrocytes. Taken together, the results suggest that HFD may cause neuronal and astrocytic damage, which indirectly proposes that CNS pathologies involving neuroinflammation and reactive gliosis could be prevented via the diet regimen.

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Section: Discussionsupporting

confidence: 71%

Peer Review #2 of "Palmitic acid induces neurotoxicity and gliatoxicity in SH-SY5Y human neuroblastoma and T98G human glioblastoma cells (v0.1)"

2018

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“…In the case of astrocytes, PA decreases glucose uptake and lactate release [97]. Furthermore, it increases the production of proinflammatory cytokines [94,98] and ROS in astrocytes [99,100]. As a consequence of these alterations, PA induces apoptosis and decreases cell viability of astrocytes [99,101].…”

Section: Involvement Of Astrocyte Autophagy In Systemic Metabolismmentioning

confidence: 99%

The Contribution of Astrocyte Autophagy to Systemic Metabolism

Ortiz-Rodriguez

Arévalo

2020

IJMS

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Autophagy is an essential mechanism to maintain cellular homeostasis. Besides its role in controlling the quality of cytoplasmic components, it participates in nutrient obtaining and lipid mobilization under stressful conditions. Furthermore, autophagy is involved in the regulation of systemic metabolism as its blockade in hypothalamic neurons can affect the central regulation of metabolism and impact body energy balance. Moreover, hypothalamic autophagy can be altered during obesity, one of the main alterations of metabolism nowadays. In this review, we focus on the role of astrocytes, essential cells for brain homeostasis, which represent key metabolic regulators. Astrocytes can sense metabolic signals in the hypothalamus and modulate systemic functions as glucose homeostasis and feeding response. Moreover, the response of astrocytes to obesity has been widely studied. Astrocytes are important mediators of brain inflammation and can be affected by increased levels of saturated fatty acids associated with obesity. Although autophagy plays important roles for astrocyte homeostasis and functioning, the contribution of astrocyte autophagy to systemic metabolism has not been analyzed yet. Furthermore, how obesity can impact astrocyte autophagy is poorly understood. More studies are needed in order to understand the contribution of astrocyte autophagy to metabolism.

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“…Palmitic acid‐stimulated ROS production has been studied in different cells including astrocytes . In the present study, we report for the first time that NDP‐MSH, through MC4R, reduces ROS levels in astrocytes challenged with PA. Astrocytes are key players in defence against oxidative insults .…”

Section: Discussionmentioning

confidence: 49%

“…Palmitic acid (PA) is the most abundant free fatty acid found in food, and in vitro studies indicate that PA induces tumour necrosis factor (TNF)‐α, interleukin (IL)‐1β and IL‐6 release in astrocytes and microglia . In addition, PA increases ROS production in astrocytes . In the hypothalamus, astroglial cells are involved in the detection and transport of nutrients and also express receptors for hormones and neuropeptides whose activation directly affects the neurones that control metabolic homeostasis .…”

Section: Introductionmentioning

confidence: 99%

NDP‐MSH reduces oxidative damage induced by palmitic acid in primary astrocytes

Ramírez

Saba

Turati

et al. 2019

J Neuroendocrinology

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Recent findings relate obesity to inflammation in key hypothalamic areas for body weight control. Hypothalamic inflammation has also been related to oxidative stress.Palmitic acid (PA) is the most abundant free fatty acid found in food, and in vitro studies indicate that it triggers a pro-inflammatory response in the brain.Melanocortins are neuropeptides with proven anti-inflammatory and neuroprotective action mediated by melanocortin receptor 4 (MC4R), but little is known about the effect of melanocortins on oxidative stress. The aim of this study was to investigate whether melanocortins could alleviate oxidative stress induced by a high fat diet (HFD) model. We found that NDP-MSH treatment decreased PA-induced reactive oxygen species production in astrocytes, an effect blocked by the MC4R inhibitor JKC363. NDP-MSH abolished nuclear translocation of Nrf2 induced by PA and blocked the inhibitory effect of PA on superoxide dismutase (SOD) activity and glutathione levels while it also per se increased activity of SOD and γ-glutamate cysteine ligase (γ-GCL) antioxidant enzymes. However, HFD reduced hypothalamic MC4R and brain derived neurotrophic factor mRNA levels, thereby preventing the neuroprotective mechanism induced by melanocortins. K E Y W O R D Sastrocytes, high-fat diet, MC4R, oxidative stress, palmitic acid

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Palmitic acid-induced lipotoxicity and protection by (+)-catechin in rat cortical astrocytes

Abstract: Our results suggest that PA-induced cytotoxicity in astrocytes may involve ROS generation and MMP collapse, which can be prevented by (+)-catechin.

Cited by 42 publications

References 26 publications

Peer Review #2 of "Palmitic acid induces neurotoxicity and gliatoxicity in SH-SY5Y human neuroblastoma and T98G human glioblastoma cells (v0.1)"

Peer Review #2 of "Palmitic acid induces neurotoxicity and gliatoxicity in SH-SY5Y human neuroblastoma and T98G human glioblastoma cells (v0.1)"

The Contribution of Astrocyte Autophagy to Systemic Metabolism

NDP‐MSH reduces oxidative damage induced by palmitic acid in primary astrocytes

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