Cholesterol overload induces apoptosis in SH-SY5Y human neuroblastoma cells through the up regulation of flotillin-2 in the lipid raft and the activation of BDNF/Trkb signaling

Huang, Yen Ning; Lin, Chin-Kai; Liao, Hsiang I.; Liu, Chin Yu; Chen, Yue Hua; Chiu, Wan‐Chun; Lin, Shyh Hsiang

doi:10.1016/j.neuroscience.2016.04.043

Cited by 21 publications

(15 citation statements)

References 50 publications

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“…It was previously reported that toxic concentrations (12–25 μM) of cholesterol impair BDNF secretion by undifferentiated SH‐SY5Y (Huang et al, ). Here we investigated whether cholesterol, in a concentration range not affecting cell viability, influences BDNF expression and synthesis by differentiated SH‐SY5Y neurons.…”

Section: Resultsmentioning

confidence: 97%

Brain‐derived neurotrophic factor modulates cholesterol homeostasis and Apolipoprotein E synthesis in human cell models of astrocytes and neurons

Spagnuolo

Donizetti

Iannotta

et al. 2018

Journal Cellular Physiology

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In the central nervous system, cholesterol is critical to maintain membrane plasticity, cellular function, and synaptic integrity. In recent years, much attention was focused on the role of cholesterol in brain since a breakdown of cholesterol metabolism has been associated with different diseases. Brain-derived neurotrophic factor (BDNF) was previously reported to elicit cholesterol biosynthesis and promote the accumulation of presynaptic proteins in cholesterol-rich lipid rafts, but no data are available on its ability to modulate physiological mechanisms involved in cholesterol homeostasis. Major aim of this research was to investigate whether BDNF influences cholesterol homeostasis, focusing on the effect of the neurotrophin on Apolipoprotein E (ApoE) synthesis, cholesterol efflux from astrocytes and cholesterol incorporation into neurons. Our results show that BDNF significantly stimulates cholesterol efflux by astrocytes, as well as ATP binding cassette A1 (ABCA1) transporter and ApoE expression. Conversely, cholesterol uptake in neurons was downregulated by BDNF. This effect was associated with the increase of Liver X Receptor (LXR)-beta expression in neuron exposed to BDNF. The level of apoptosis markers, that is, cleaved caspase 3 and poly ADP ribose polymerase (PARP), was found increased in neurons treated with high cholesterol, but significantly lower when the cells were exposed to cholesterol in the presence of BDNF, thus suggesting a neuroprotective role of the neurotrophin, likely through its reducing effect of neuronal cholesterol uptake. Interestingly, cholesterol stimulates BDNF production by neurons. Overall, our findings evidenced a novel role of BDNF in the modulation of ApoE and cholesterol homeostasis in glial and neuronal cells.

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Section: Resultsmentioning

confidence: 97%

Brain‐derived neurotrophic factor modulates cholesterol homeostasis and Apolipoprotein E synthesis in human cell models of astrocytes and neurons

Spagnuolo

Donizetti

Iannotta

et al. 2018

Journal Cellular Physiology

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“…Various mechanisms for FXR-mediated regulation of the CREB-BDNF pathway have been reported previously. FXR may reduce the lipid levels in the brain, as it was shown that hyperlipidemic and hypercholesterolemic status decreased BDNF expression [31,32]. Z-guggulsterone attenuated symptoms in a scopolamine-lesioned AD mouse model by augmentation of the CREB-BDNF signal, while the direct interaction of FXR and CREB was not mentioned in this report [22].…”

Section: Discussionmentioning

confidence: 94%

Farnesoid X Receptor (FXR) Aggravates Amyloid-β-Triggered Apoptosis by Modulating the cAMP-Response Element-Binding Protein (CREB)/Brain-Derived Neurotrophic Factor (BDNF) Pathway In Vitro

Chen

Guo

et al. 2019

Med Sci Monit

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Background: Alzheimer's disease (AD), which results in cognitive deficits, usually occurs in older people and is mainly caused by amyloid beta (Ab) deposits and neurofibrillary tangles. The bile acid receptor, farnesoid X receptor (FXR), has been extensively studied in cardiovascular diseases and digestive diseases. However, the role of FXR in AD is not yet understood. The purpose of the present study was to investigate the mechanism of FXR function in AD. Material/Methods: Lentivirus infection, flow cytometry, real-time PCR, and western blotting were used to detect the gain or loss of FXR in cell apoptosis induced by Ab. Co-immunoprecipitation was used to analyze the molecular partners involved in Ab-induced apoptosis. Results: We found that the mRNA and protein expression of FXR was enhanced in Ab-triggered neuronal apoptosis in differentiated SH-SY5Y cells and in mouse hippocampal neurons. Overexpression of FXR aggravated Ab-triggered neuronal apoptosis in differentiated SH-SY5Y cells, and this effect was further increased by treatment with the FXR agonist 6ECDCA. Molecular mechanism analysis by co-immunoprecipitation and immunoblotting revealed that FXR interacted with the cAMP-response element-binding protein (CREB), leading to decreased CREB and brain-derived neurotrophic factor (BDNF) protein levels. Low expression of FXR mostly reversed the Ab-triggered neuronal apoptosis effect and prevented the reduction in CREB and BDNF. Conclusions: These data suggest that FXR regulates Ab-induced neuronal apoptosis, which may be dependent on the CREB/BDNF signaling pathway in vitro.

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“…44,45 In contrast, other studies also reported that cholesterol inhibited proliferation and invasion of some cancer cells and induced apoptosis. [46][47][48] Although in orthotopic and subcutaneous implantation models, no apparent change in cholesterol or its metabolites level was detected in Hep1-6 tumors from the HCD group (data not shown), other possible mechanisms may also contribute to the antihepatoma effect induced by high serum cholesterol level, which we have not yet seen due to technical limitations.…”

Section: Discussionmentioning

confidence: 99%

High Serum Levels of Cholesterol Increase Antitumor Functions of Nature Killer Cells and Reduce Growth of Liver Tumors in Mice

et al. 2020

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Cholesterol overload induces apoptosis in SH-SY5Y human neuroblastoma cells through the up regulation of flotillin-2 in the lipid raft and the activation of BDNF/Trkb signaling

Cited by 21 publications

References 50 publications

Brain‐derived neurotrophic factor modulates cholesterol homeostasis and Apolipoprotein E synthesis in human cell models of astrocytes and neurons

Brain‐derived neurotrophic factor modulates cholesterol homeostasis and Apolipoprotein E synthesis in human cell models of astrocytes and neurons

Farnesoid X Receptor (FXR) Aggravates Amyloid-β-Triggered Apoptosis by Modulating the cAMP-Response Element-Binding Protein (CREB)/Brain-Derived Neurotrophic Factor (BDNF) Pathway In Vitro

High Serum Levels of Cholesterol Increase Antitumor Functions of Nature Killer Cells and Reduce Growth of Liver Tumors in Mice

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