Premium
Nerve growth factor ( NGF ) and pro‐ NGF increase low‐density lipoprotein ( LDL ) receptors in neuronal cells partly by different mechanisms: role of LDL in neurite outgrowth
Author(s) -
Do Hai Thi,
Bruelle Céline,
Pham Dan Duc,
Jauhiainen Matti,
Eriksson Ove,
Korhonen Laura T.,
Lindholm Dan
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13397
Subject(s) - nerve growth factor , endocrinology , medicine , neurite , ldl receptor , receptor , neurotrophin , chemistry , microbiology and biotechnology , biology , lipoprotein , cholesterol , biochemistry , in vitro
Low‐density lipoprotein receptors ( LDLR s) mediate the uptake of lipoprotein particles into cells, as studied mainly in peripheral tissues. Here, we show that nerve growth factor ( NGF ) increases LDLR levels in PC 6.3 cells and in cultured septal neurons from embryonic rat brain. Study of the mechanisms showed that NGF enhanced transcription of the LDLR gene, acting mainly via Tropomyosin receptor kinase A receptors. Simvastatin, a cholesterol‐lowering drug, also increased the LDLR expression in PC 6.3 cells. In addition, pro‐ NGF and pro‐brain‐derived neurotrophic factor, acting via the p75 neurotrophin receptor (p75 NTR ) also increased LDLR s. We further observed that Myosin Regulatory Light Chain‐Interacting Protein/Inducible Degrader of the LDLR (Mylip/Idol) was down‐regulated by pro‐ NGF , whereas the other LDLR regulator, proprotein convertase subtilisin kexin 9 ( PCSK 9) was not significantly changed. On the functional side, NGF and pro‐ NGF increased lipoprotein uptake by neuronal cells as shown using diacetyl‐labeled LDL . The addition of serum‐derived lipoprotein particles in conjunction with NGF or simvastatin enhanced neurite outgrowth. Collectively, these results show that NGF and simvastatin are able to stimulate lipoprotein uptake by neurons with a positive effect on neurite outgrowth. Increases in LDLR s and lipoprotein particles in neurons could play a functional role during brain development, in neuroregeneration and after brain injuries.Nerve growth factor (NGF) and pro‐NGF induce the expression of low‐density lipoprotein receptors (LDLRs) in neuronal cells leading to increased LDLR levels. Pro‐NGF also down‐regulated myosin regulatory light chain‐interacting protein/inducible degrader of the LDLR (Mylip/Idol) that is involved in the degradation of LDLRs. NGF acts mainly via Tropomyosin receptor kinase A (TrkA) receptors, whereas pro‐NGF stimulates p75 neurotrophin receptor (p75NTR). Elevated LDLRs upon NGF and pro‐NGF treatments enhanced lipoprotein uptake by neurons. Addition of LDL particles further led to the stimulation of neurite outgrowth in PC6.3 cells after NGF or simvastatin treatments, suggesting a stimulatory role of lipoproteins on neuronal differentiation. In contrast, pro‐NGF had no effect on neurite outgrowth either in the absence or presence of LDL particles. The precise mechanisms by which increased lipoproteins uptake can affect neurite outgrowth warrant further studies.