Neurotrophins as Key Regulators of Cell Metabolism: Implications for Cholesterol Homeostasis

Abstract

Neurotrophins constitute a family of growth factors initially characterized as predominant mediators of nervous system development, neuronal survival, regeneration and plasticity. Their biological activity is promoted by the binding of two different types of receptors, leading to the generation of multiple and variegated signaling cascades in the target cells. Increasing evidence indicates that neurotrophins are also emerging as crucial regulators of metabolic processes in both neuronal and non-neuronal cells. In this context, it has been reported that neurotrophins affect redox balance, autophagy, glucose homeostasis and energy expenditure. Additionally, the trophic support provided by these secreted factors may involve the regulation of cholesterol metabolism. In this review, we examine the neurotrophins' signaling pathways and their effects on metabolism by critically discussing the most up-to-date information. In particular, we gather experimental evidence demonstrating the impact of these growth factors on cholesterol metabolism.

Keywords: BDNF; NGF; TrkA; TrkB; cholesterol; metabolism; neurotrophins; p75NTR.

Figure 1

Signaling pathways mediated by neurotrophins’ binding to their receptors. Neurotrophins bind to two main receptor types: Trk receptors and p75NTR. Pro-neurotrophins (proNT) processing generates mature neurotrophins (mNT). Upon mNT stimulation, Trk receptors undergo autophosphorylation events, and recruit adaptor proteins responsible for the activation of MAPKs, PI3K and PLCγ signaling cascades, involved in several neuronal functions such as neurite outgrowth. mNT may also bind to p75NTR, stimulating its proteolysis which releases the intracellular domain (p75ICD) that is essential for signalling and for the regulation of gene transcription. p75NTR activation by mNT may promote neuronal survival by inducing NF-kB signaling. In addition, Necdin recruitment to p75NTR may regulate cell cycle progression and differentiation in a variety of cell types, whereas the interaction with PDE4 and PKA is involved in the regulation of energy balance. Importantly, in dependence on the cell context, p75NTR activation by mNT is able to potentiate the activation of Trk receptors. On the other hand, the binding of proNT to the p75NTR/Sortilin complex enhances the activation of cell-death-related pathways. When p75NTR interacts with NOGO/LINGO1, the recruitment of Rho GDI leads to the activation of RhoA, which in turn determines the inhibition of neurite outgrowth in neurons. FAP1, FAS-associated phosphatase 1; GAB1, GRB2 Associated Binding Protein 1; Grb2, growth factor receptor-bound protein 2; IRS 1/2, insulin receptor substrate 1/2; JNK, c-Jun N-terminal kinases; LINGO1, leucine-rich repeat and Immunoglobin-like domain-containing protein 1; NADE, p75NTR-associated cell death executor; p75NTR, p75 neurotrophin receptor; NRAGE, neurotrophin receptor-interacting MAGE homologue; NRIF, neurotrophin receptor-interacting factor; PDE4, phosphodiesterase 4; PDK, phosphoinositide-dependent kinase; PKA, protein kinase A; PLCγ phospholipase Cγ; RhoA, Ras homolog family member A; RIP2, receptor-interacting protein 2; Shc, SRC homology domain-containing protein; SOS, son of sevenless; TRAF6, TNF receptor-associated factor 6; Trk, tropomyosin receptor kinase. This figure is created with BioRender.

Figure 2

Cholesterol metabolism in the CNS. Cholesterol in the brain is assured by de novo biosynthesis requiring a multistep pathway. HMGCR is responsible for the conversion of HMG-CoA in MVA and represents the key and rate-limiting step. In the adult CNS, neurons reduce their own cholesterol synthesis and import this lipid from astrocytes, which secrete apoE rich-lipoproteins through ABCA1 transporters. ABCA1 and apoE transcription is elicited by LXR, whose activity is modulated by 24-OHC. Cholesterol uptake in neurons is ensured by LDLr and LRP1, particularly expressed on the cell membranes of neurons. Cholesterol excretion in the brain is mainly promoted by its conversion to 24-OHC catalyzed by CYP46. Abbreviations: 24-OHC, 24(S)-hydroxycholesterol; ABCA1, ATP-binding cassette transporter A1; apoE, apolipoprotein E; BCEC, brain capillary endothelial cells; CYP46, cholesterol 24-hydroxylase; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; LDLR, LDL receptor; LRP1, LDLr-related protein 1; LXR, liver X receptor; MVA, mevalonate; SR-B1, scavenger receptor class B member 1. This figure is created with BioRender.