PMID- 29323721 OWN - NLM STAT- MEDLINE DCOM- 20190930 LR - 20190930 IS - 1097-4652 (Electronic) IS - 0021-9541 (Linking) VI - 233 IP - 9 DP - 2018 Sep TI - Brain-derived neurotrophic factor modulates cholesterol homeostasis and Apolipoprotein E synthesis in human cell models of astrocytes and neurons. PG - 6925-6943 LID - 10.1002/jcp.26480 [doi] AB - 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. CI - (c) 2018 Wiley Periodicals, Inc. FAU - Spagnuolo, Maria S AU - Spagnuolo MS AD - Department of Bio-Agrofood Science, Institute for the Animal Production System in Mediterranean Environment, National Research Council, Naples, Italy. FAU - Donizetti, Aldo AU - Donizetti A AD - Department of Biology, University of Naples Federico II, Naples, Italy. FAU - Iannotta, Lucia AU - Iannotta L AD - Department of Biology, University of Naples Federico II, Naples, Italy. FAU - Aliperti, Vincenza AU - Aliperti V AD - Department of Biology, University of Naples Federico II, Naples, Italy. FAU - Cupidi, Chiara AU - Cupidi C AD - Centro Regionale di Neurogenetica, via Perugini, ASP Catanzaro, Lamezia Terme (CZ), Italy. FAU - Bruni, Amalia C AU - Bruni AC AD - Centro Regionale di Neurogenetica, via Perugini, ASP Catanzaro, Lamezia Terme (CZ), Italy. FAU - Cigliano, Luisa AU - Cigliano L AUID- ORCID: 0000-0002-5491-9659 AD - Department of Biology, University of Naples Federico II, Naples, Italy. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180325 PL - United States TA - J Cell Physiol JT - Journal of cellular physiology JID - 0050222 RN - 0 (ATP Binding Cassette Transporter 1) RN - 0 (Apolipoproteins E) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Liver X Receptors) RN - 97C5T2UQ7J (Cholesterol) SB - IM MH - ATP Binding Cassette Transporter 1/metabolism MH - Apolipoproteins E/*biosynthesis MH - Apoptosis/drug effects MH - Astrocytes/drug effects/*metabolism MH - Brain-Derived Neurotrophic Factor/*pharmacology MH - Cell Line, Tumor MH - Cholesterol/*metabolism MH - Homeostasis/*drug effects MH - Humans MH - Liver X Receptors/metabolism MH - MAP Kinase Signaling System/drug effects MH - Middle Aged MH - Models, Biological MH - Neurons/drug effects/*metabolism MH - Prefrontal Cortex/metabolism OTO - NOTNLM OT - Apolipoprotein E OT - apoptosis OT - astrocytes OT - brain-derived neurotrophic factor OT - cholesterol OT - neurons EDAT- 2018/01/13 06:00 MHDA- 2019/10/01 06:00 CRDT- 2018/01/12 06:00 PHST- 2017/07/28 00:00 [received] PHST- 2018/01/05 00:00 [accepted] PHST- 2018/01/13 06:00 [pubmed] PHST- 2019/10/01 06:00 [medline] PHST- 2018/01/12 06:00 [entrez] AID - 10.1002/jcp.26480 [doi] PST - ppublish SO - J Cell Physiol. 2018 Sep;233(9):6925-6943. doi: 10.1002/jcp.26480. Epub 2018 Mar 25.