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.

The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis

“…Similarity, thyroid hormones (TH) play an important role in the development of human brain, by upregulating the expression of specific DHCR24 genes in neuronal precursors [ 10 ]. Moreover, it has been found that IGF1 and nerve growth factor (NGF) induced upregulation of DHCR24 expression, and conversely, the inhibition of IGF signaling downregulated the expression of DHCR24 [ 22 , 42 ]. On the contrary, dexamethasone could obviously decrease the expression of genes involved in cholesterol synthesis genes, such as squalene epoxidase (SQLE) and DHCR24 [ 58 ].…”

“…On the contrary, dexamethasone could obviously decrease the expression of genes involved in cholesterol synthesis genes, such as squalene epoxidase (SQLE) and DHCR24 [ 58 ]. Besides, with aging, there is a progressive, age-dependent decline in the level of many important neurotrophic factors, such as estrogen, androgen, insulin, NGF and IGFs, in the brain of aged rodents and AD patients [ 19 , 22 , 112 ]. Thus, evidences suggest that the downregulation of DHCR24 induced by the depletion of neurosteroids and neurotrophic factors in the brain might play a pivotal pathological role in neurodegenerative diseases.…”

“…Importantly, DHCR24 can also synergistically control the activity of 7-dehydrocholesterol reductase (DHCR7), a final key enzyme in the K–R pathway, which would ensure concerted control of cholesterol synthesis [ 85 , 132 ]. From a physiological role, DHCR24 is universally regulated by sterols, dexamethasone, sex steroids, adrenocorticotropic hormone, thyroid hormone, Neurotrophins, and xenobiotics [ 22 , 87 , 112 ]. Furthermore, DHCR24 activity is also regulated by ubiquitination, phosphorylation, and epigenetic factors such as methylation and acetylation [ 64 , 87 ].…”

Leptin Receptor (rs1137101) and Brain-Derived Neurotrophic Factor (rs925946) Gene Variants Are Associated with Obesity in the Early- but Not in the Late-Onset Population of Hungarian Psoriatic Patients

“…Neurotrophins (e.g., brain-derived neurotrophic factor (BDNF]) play an important role in regulating energy and glucose homeostasis (for example, in cholesterol metabolism) not only in neuronal differentiation [ 55 ] but also in peripheral tissues [ 56 ]; therefore, they are also associated with inflammatory diseases, as well as MetS [ 57 , 58 , 59 , 60 ]. BDNF activity is mediated through the TrkB receptor [ 61 ] and the neurotrophin receptor p75 (p75NTR), also known as the low-affinity nerve growth factor receptor, which belongs to the TNF-receptor superfamily [ 62 ]. Regarding psoriasis, BDNF was found to be crucial in the maintenance of normal keratinocyte apoptosis and epidermal homeostasis [ 63 ], while p75NTR protein was found to be absent in lesional psoriasis skin.…”

Intranasal Delivery of Nerve Growth Factor in Neurodegenerative Diseases and Neurotrauma

“…The mechanisms underlying the effect of NGF on cerebral perfusion have already been addressed above. The augmented metabolism could be linked to the increased availability of nutrients, the rise in the septum-cortical circuits activity ( Tuszynski et al, 2005 ) or also to specific effects of NGF on the metabolism of NGF-responsive neurons and glia ( Rasband, 2016 ; Colardo et al, 2021 ).…”