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1.
Nucleic Acids Res ; 47(6): 2856-2870, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30698747

RESUMO

Stress hormones bind and activate the glucocorticoid receptor (GR) in many tissues including the brain. We identified arginine and glutamate rich 1 (ARGLU1) in a screen for new modulators of glucocorticoid signaling in the CNS. Biochemical studies show that the glutamate rich C-terminus of ARGLU1 coactivates multiple nuclear receptors including the glucocorticoid receptor (GR) and the arginine rich N-terminus interacts with splicing factors and binds to RNA. RNA-seq of neural cells depleted of ARGLU1 revealed significant changes in the expression and alternative splicing of distinct genes involved in neurogenesis. Loss of ARGLU1 is embryonic lethal in mice, and knockdown in zebrafish causes neurodevelopmental and heart defects. Treatment with dexamethasone, a GR activator, also induces changes in the pattern of alternatively spliced genes, many of which were lost when ARGLU1 was absent. Importantly, the genes found to be alternatively spliced in response to glucocorticoid treatment were distinct from those under transcriptional control by GR, suggesting an additional mechanism of glucocorticoid action is present in neural cells. Our results thus show that ARGLU1 is a novel factor for embryonic development that modulates basal transcription and alternative splicing in neural cells with consequences for glucocorticoid signaling.


Assuntos
Desenvolvimento Embrionário , Glucocorticoides/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Splicing de RNA/genética , Ativação Transcricional/genética , Processamento Alternativo/efeitos dos fármacos , Processamento Alternativo/genética , Animais , Animais Geneticamente Modificados , Células Cultivadas , Embrião não Mamífero , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Glucocorticoides/metabolismo , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/efeitos dos fármacos , Neurogênese/genética , Splicing de RNA/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Transativadores/fisiologia , Ativação Transcricional/efeitos dos fármacos , Peixe-Zebra
2.
Cell Physiol Biochem ; 39(4): 1648-62, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27626926

RESUMO

BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) progression to fibrosis, cirrhosis and hepatocellular carcinoma, alters the cellular composition of this organ. During late-stage NAFLD, fibrotic and possibly cancerous cells can proliferate and, like normal hepatocytes, are exposed to high concentrations of fatty acids from both surrounding tissue and circulating lipid sources. We hypothesized that primary human activated hepatic stellate cells and epithelial hepatoma (HepG2) cells respond differently to lipotoxic conditions, and investigated the mechanisms involved. METHODS: Primary activated hepatic stellate cells and HepG2 cells were exposed to pathophysiological concentrations of fatty acids and comparative studies of lipid metabolic and stress response pathways were performed. RESULTS: Both cell types remained proliferative during exposure to a combination of palmitate plus oleate reflective of the general saturated versus unsaturated fatty acid composition of western diets. However, exposure to either high palmitate or high oleate alone induced cytotoxicity in activated stellate cells, while only palmitate caused cytotoxicity in HepG2 cells. mRNA microarray and biochemical comparisons revealed that stellate cells stored markedly less fatty acids as neutral lipids, and had reduced capacity for beta-oxidation. Similar to previous observations in HepG2 cells, palmitate, but not oleate, induced ER stress and actin stress fiber formation in activated stellate cells. In contrast, oleate, but not palmitate, induced the inflammatory signal TXNIP, decreased cytoskeleton proteins, and decreased cell polarity preceding cell death in activated stellate cells. CONCLUSIONS: Palmitate-induced lipotoxicity was associated with ER stress pathways in both primary activated hepatic stellate cells and epithelial hepatoma cells, whereas high oleate caused lipotoxicity only in activated stellate cells, possibly through a distinct mechanism involving disruption of cytoskeleton components. This may have implications for optimal dietary fatty acid compositions during various stages of NAFLD.


Assuntos
Células Estreladas do Fígado/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Ácido Oleico/toxicidade , Ácido Palmítico/toxicidade , Estresse Fisiológico/efeitos dos fármacos , Transcriptoma , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Morte Celular/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Regulação da Expressão Gênica , Células Hep G2 , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/metabolismo , Humanos , Metabolismo dos Lipídeos/genética , Análise de Sequência com Séries de Oligonucleotídeos , Especificidade de Órgãos , Oxirredução , Cultura Primária de Células , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estresse Fisiológico/genética
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