NRIF is a regulator of neuronal cholesterol biosynthesis genes.
Cholesterol is a critical component of neuronal membranes, required for normal signal transduction. We showed previously that adult hippocampal neurons co-express high levels of cholesterogenic enzymes, and that their expression is under the control of the p75 neurotrophin receptor (p75NTR). Most of the cellular effects of p75NTR are mediated via interacting proteins, including neurotrophin receptor interacting factor (NRIF). In this study, we tested the hypothesis that p75NTR-dependent regulation of cholesterol and lipid biosynthesis genes is mediated by NRIF. We found that in vitro down regulation of NRIF expression decreased the mRNA for two main cholesterogenic enzymes, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr; EC 2.3.3.10) and 7-dehydrocholesterol reductase (Dhcr7; EC 1.3.1.21). Further analyses revealed that NRIF-dependent and Dhcr7-dependent transcriptional changes show a high degree of overlap, and that NRIF reduction resulted in reduced expression of sterol-sensing domain protein SCAP, followed by a decrease in mRNA levels of SRE-motif containing genes (HMGCR, FASN, SREBP2, S1P, and SQS1). Finally, a reduction in cholesterol biosynthesis-related gene expression was also observed in hippocampal tissue of mice with NRIF deletion. Our combined in vitro and in vivo studies suggest that hippocampal neuronal cholesterol biosynthesis is regulated through the p75NTR interacting factor NRIF.
Korade
Zeljka
Z
Department of Biochemistry, Vanderbilt University School of Medicine, 8124A MRB III, Nashville, TN 37232, USA. zeljka.korade@vanderbilt.edu
Kenchappa
Rajappa S
RS
Mirnics
Karoly
K
Carter
Bruce D
BD
D000214:Acyl Coenzyme A / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis*; D004268:DNA-Binding Proteins; D015971:Gene Expression Regulation, Enzymologic; D006624:Hippocampus / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D009447:Neuroblastoma; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism
D000214:Acyl Coenzyme A; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D020800:Receptor, Nerve Growth Factor; C402289:Zfp110 protein, mouse; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D002784:Cholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase