Novel roles of p75 neurotrophin receptor in Low-density lipoprotein receptor regulation and lipid signaling

Lipid disturbances reflect the dysregulation of molecular pathways associated with metabolic syndromes and neurological diseases like Alzheimer’s disease and Huntington’s disease. Several factors underlay the pathogenesis of lipid disorders, including accumulation of lipids, disturbed cell signaling, inflammation, mitochondria dysfunctions, ER stress and activation of cell death pathways. Here we have studied the roles of the neurotrophin, NGF and pro-NGF, and their receptor, p75NTR, a member of the tumor necrosis factor (TNF) superfamily, in lipid regulation. NGF and p75NTR have been previously studied in the nervous system but they are also expressed in non-neuronal cells, particularly after tissue injury and inflammation. In our study, we have used various cell and molecular biology methods, as well as protein methods, to elucidate the function of p75NTR in hepatocytes and neuronal cells. We have further employed p75NTR gene-deleted mice, and CRISPR/Cas9-mediated gene inactivation in human hepatocyte cells to elucidate the mechanisms of p75NTR in LDLR regulation. We have thus identified a molecular pathway by which NGF and pro-NGF influence SREBP activation leading to altered LDLR regulation and LDL uptake involving caspase-2/caspase-3 actions in Huh7 hepatocyte cells. Furthermore, we provide insight into the influence of LDL particles on neurite outgrowth in neuronal cells. RNA-sequencing analysis of wild-type and p75NTR-KO mice has demonstrated further that lipogenic genes are altered in the absence of p75NTR. There was also a down-regulation of serum cholesterol in p75NTR-KO mice in comparison with controls. Our findings showed further that NGF and pro-NGF are elevated, together with an increase in LDLRs in ob/ob and db/db mouse livers. This work will add to our understanding of p75NTR in health and disease, and may open up new possibilities to identify novel therapeutics to combat fatty liver and various metabolic disorders.