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1.
J Biol Chem ; 291(20): 10747-58, 2016 May 13.
Article in English | MEDLINE | ID: mdl-26984409

ABSTRACT

Nerve growth factor (NGF) influences the survival and differentiation of a specific population of neurons during development, but its role in non-neuronal cells has been less studied. We observed here that NGF and its pro-form, pro-NGF, are elevated in fatty livers from leptin-deficient mice compared with controls, concomitant with an increase in low density lipoprotein receptors (LDLRs). Stimulation of mouse primary hepatocytes with NGF or pro-NGF increased LDLR expression through the p75 neurotrophin receptor (p75NTR). Studies using Huh7 human hepatocyte cells showed that the neurotrophins activate the sterol regulatory element-binding protein-2 (SREBP2) that regulates genes involved in lipid metabolism. The mechanisms for this were related to stimulation of p38 mitogen-activated protein kinase (p38 MAPK) and activation of caspase-3 and SREBP2 cleavage following NGF and pro-NGF stimulations. Cell fractionation experiments showed that caspase-3 activity was increased particularly in the membrane fraction that harbors SREBP2 and caspase-2. Experiments showed further that caspase-2 interacts with pro-caspase-3 and that p38 MAPK reduced this interaction and caused caspase-3 activation. Because of the increased caspase-3 activity, the cells did not undergo cell death following p75NTR stimulation, possibly due to concomitant activation of nuclear factor-κB (NF-κB) pathway by the neurotrophins. These results identify a novel signaling pathway triggered by ligand-activated p75NTR that via p38 MAPK and caspase-3 mediate the activation of SREBP2. This pathway may regulate LDLRs and lipid uptake particularly after injury or during tissue inflammation accompanied by an increased production of growth factors, including NGF and pro-NGF.


Subject(s)
Hepatocytes/metabolism , Nerve Tissue Proteins/metabolism , Receptors, Nerve Growth Factor/metabolism , Sterol Regulatory Element Binding Protein 2/metabolism , Animals , Caspase 3/deficiency , Caspase 3/genetics , Caspase 3/metabolism , Cell Line , Fatty Liver/metabolism , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Obese , Nerve Growth Factor/metabolism , Receptors, LDL/metabolism , Receptors, Nerve Growth Factor/deficiency , Receptors, Nerve Growth Factor/genetics , Signal Transduction , p38 Mitogen-Activated Protein Kinases/metabolism
2.
J Neurochem ; 136(2): 306-15, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26484803

ABSTRACT

Low-density lipoprotein receptors (LDLRs) 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 PC6.3 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 PC6.3 cells. In addition, pro-NGF and pro-brain-derived neurotrophic factor, acting via the p75 neurotrophin receptor (p75NTR) also increased LDLRs. 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 (PCSK9) 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 LDLRs 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.


Subject(s)
Lipoproteins, LDL/metabolism , Neurites/physiology , Neurons/cytology , Neurons/metabolism , Receptors, LDL/metabolism , Receptors, Nerve Growth Factor/metabolism , Animals , Antibodies/pharmacology , Benzoates/pharmacology , Benzylamines/pharmacology , Carbazoles/pharmacology , Cells, Cultured , Culture Media, Serum-Free/pharmacology , Embryo, Mammalian , Enzyme Inhibitors/pharmacology , Gene Expression Regulation/drug effects , Humans , Indole Alkaloids/pharmacology , Nerve Growth Factor/pharmacology , Nerve Growth Factors/pharmacology , Neurites/drug effects , Neurons/drug effects , Protein Precursors/pharmacology , Rats , Rats, Wistar , Receptors, LDL/immunology , Septum of Brain/cytology , Simvastatin/pharmacology
3.
Neuropharmacology ; 102: 266-75, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26631533

ABSTRACT

Mitochondrial dysfunction has been linked to several neurodegenerative diseases such as Parkinson's disease (PD). Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master gene for mitochondrial biogenesis and has been shown to be neuroprotective in models of PD. In this work we have studied the mechanisms by which peroxisome proliferator-activated receptor-γ (PPARγ) selective agonist N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino)ethyl]-l-tyrosine hydrate (GW1929) acts on human dopaminergic neurons in culture. Data showed that GW1929 increased the viability of human dopaminergic neurons and protected them against oxidative stress induced by H2O2 and the mitochondrial toxin Rotenone. The enhanced resilience of the neurons was attributed to increased levels of mitochondrial antioxidants and of PGC-1α. GW1929 treatment further increased cell respiration, mitochondrial biogenesis and sirtuin-1 (SIRT1) expression in the human dopaminergic neurons. Phosphorylation of cAMP responsive element-binding protein (CREB) was also robustly increased in GW1929-treated cells. Together these results show that the PPARγ agonist GW1929 influences CREB signaling and PGC-1α activities in the human dopaminergic neurons contributing to an increased cell viability. This supports the view that drugs acting on the PPARγ-PGC-1α signaling in neurons may have beneficial effects in PD and possible also in other brain disorders.


Subject(s)
Benzophenones/pharmacology , Cyclic AMP Response Element-Binding Protein/metabolism , Dopaminergic Neurons/drug effects , Neuroprotective Agents/pharmacology , PPAR gamma/agonists , Transcription Factors/metabolism , Tyrosine/analogs & derivatives , Cell Line , Dopaminergic Neurons/metabolism , Humans , Mitochondria/drug effects , Mitochondria/metabolism , Organelle Biogenesis , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Phosphorylation/drug effects , Sirtuin 1/metabolism , Tyrosine/pharmacology
4.
Springerplus ; 3: 2, 2014.
Article in English | MEDLINE | ID: mdl-25932355

ABSTRACT

Mitochondrial dysfunctions accompany several neurodegenerative disorders and contribute to disease pathogenesis among others in Parkinson's disease (PD). Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a major regulator of mitochondrial functions and biogenesis, and was suggested as a therapeutic target in PD. PGC-1α is regulated by both transcriptional and posttranslational events involving also the action of growth factors. Fibroblast growth factor-21 (FGF21) is a regulator of glucose and fatty acid metabolism in the body but little is known about its action in the brain. We show here that FGF21 increased the levels and activity of PGC-1α and elevated mitochondrial antioxidants in human dopaminergic cells in culture. The activation of PGC-1α by FGF21 occurred via the NAD(+)-dependent deacetylase Sirtuin-1 (SIRT1) subsequent to an increase in the enzyme, nicotinamide phosphoribosyltransferase (Nampt). FGF21 also enhanced mitochondrial respiratory capacity in human dopaminergic neurons as shown in real-time analyses of living cells. FGF21 is present in the brain including midbrain and is expressed by glial cells in culture. These results show that FGF21 activates PGC-1α and increases mitochondrial efficacy in human dopaminergic neurons suggesting that FGF21 could potentially play a role in dopaminergic neuron viability and in PD.

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