title: p75 Neurotrophin Receptor Signaling Activates Sterol Regulatory Element-binding Protein-2 in Hepatocyte Cells via p38 Mitogen-activated Protein Kinase and Caspase-3.
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.
authors.affiliation: From the Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, P. O. Box 63, Helsinki FIN-00014, Finland, the Minerva Foundation Institute for Medical Research, Biomedicum-2, Tukholmankatu 8, FIN-00290 Helsinki, Finland.
authors.forename: Dan Duc
authors.initials: DD
authors.lastname: Pham
authors.affiliation: From the Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, P. O. Box 63, Helsinki FIN-00014, Finland, the Minerva Foundation Institute for Medical Research, Biomedicum-2, Tukholmankatu 8, FIN-00290 Helsinki, Finland.
authors.forename: Hai Thi
authors.initials: HT
authors.lastname: Do
authors.affiliation: From the Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, P. O. Box 63, Helsinki FIN-00014, Finland, the Minerva Foundation Institute for Medical Research, Biomedicum-2, Tukholmankatu 8, FIN-00290 Helsinki, Finland.
authors.forename: Céline
authors.initials: C
authors.lastname: Bruelle
authors.affiliation: Biochemistry and Cell Biology, Department of Veterinary Biosciences, P. O. Box 66, University of Helsinki, Helsinki FIN-00014, Finland.
authors.forename: Jyrki P
authors.initials: JP
authors.lastname: Kukkonen
authors.affiliation: From the Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, P. O. Box 63, Helsinki FIN-00014, Finland.
authors.forename: Ove
authors.initials: O
authors.lastname: Eriksson
authors.affiliation: From the Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, P. O. Box 63, Helsinki FIN-00014, Finland, the Minerva Foundation Institute for Medical Research, Biomedicum-2, Tukholmankatu 8, FIN-00290 Helsinki, Finland.
authors.forename: Isabel
authors.initials: I
authors.lastname: Mogollón
authors.affiliation: From the Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, P. O. Box 63, Helsinki FIN-00014, Finland, the Minerva Foundation Institute for Medical Research, Biomedicum-2, Tukholmankatu 8, FIN-00290 Helsinki, Finland.
authors.forename: Laura T
authors.initials: LT
authors.lastname: Korhonen
authors.affiliation: the Research Program in Developmental Biology, Institute of Biotechnology, University of Helsinki, P. O. Box 65, Helsinki FIN-00014, Finland, and the Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia.
authors.forename: Urmas
authors.initials: U
authors.lastname: Arumäe
authors.affiliation: From the Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, P. O. Box 63, Helsinki FIN-00014, Finland, the Minerva Foundation Institute for Medical Research, Biomedicum-2, Tukholmankatu 8, FIN-00290 Helsinki, Finland, dan.lindholm@helsinki.fi.
authors.forename: Dan
authors.initials: D
authors.lastname: Lindholm
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D005234:Fatty Liver / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D020932:Nerve Growth Factor / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D011973:Receptors, LDL; D017475:Receptors, Nerve Growth Factor; C497390:SREBF2 protein, human; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; C517634:Ngfr protein, mouse; D020932:Nerve Growth Factor; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: LDLR; NGF; SREBP2; caspase; hepatocyte; neurotrophin; p38 MAPK; p75 neurotrophin receptor; pro-NGF