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1.
FASEB J ; 30(2): 798-812, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26487695

RESUMO

The eukaryotic translation initiation factor 2α (eIF2α) phosphorylation-dependent integrated stress response (ISR), a component of the unfolded protein response, has long been known to regulate intermediary metabolism, but the details are poorly worked out. We report that profiling of mRNAs of transgenic mice harboring a ligand-activated skeletal muscle-specific derivative of the eIF2α protein kinase R-like ER kinase revealed the expected up-regulation of genes involved in amino acid biosynthesis and transport but also uncovered the induced expression and secretion of a myokine, fibroblast growth factor 21 (FGF21), that stimulates energy consumption and prevents obesity. The link between the ISR and FGF21 expression was further reinforced by the identification of a small-molecule ISR activator that promoted Fgf21 expression in cell-based screens and by implication of the ISR-inducible activating transcription factor 4 in the process. Our findings establish that eIF2α phosphorylation regulates not only cell-autonomous proteostasis and amino acid metabolism, but also affects non-cell-autonomous metabolic regulation by induced expression of a potent myokine.


Assuntos
Aminoácidos/metabolismo , Metabolismo Energético/fisiologia , Fator de Iniciação 2 em Eucariotos/metabolismo , Fatores de Crescimento de Fibroblastos/biossíntese , Regulação da Expressão Gênica/fisiologia , Músculo Esquelético/metabolismo , Resposta a Proteínas não Dobradas/fisiologia , Aminoácidos/genética , Animais , Fator de Iniciação 2 em Eucariotos/genética , Fatores de Crescimento de Fibroblastos/genética , Humanos , Camundongos , Camundongos Transgênicos , Músculo Esquelético/citologia , Fosforilação/genética
2.
Mol Biol Cell ; 21(17): 2975-86, 2010 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-20631254

RESUMO

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates homeostatic responses collectively termed the unfolded protein response. Among the three principal signaling pathways operating in mammals, activating transcription factor (ATF)6alpha plays a pivotal role in transcriptional induction of ER-localized molecular chaperones and folding enzymes as well as components of ER-associated degradation, and thereby mouse embryonic fibroblasts deficient in ATF6alpha are sensitive to ER stress. However, ATF6alpha-knockout mice show no apparent phenotype under normal growing conditions. In this report, we burdened mice with intraperitoneal injection of the ER stress-inducing reagent tunicamycin and found that wild-type mice were able to recover from the insult, whereas ATF6alpha-knockout mice exhibited liver dysfunction and steatosis. Thus, ATF6alpha-knockout mice accumulated neutral lipids in the liver such as triacylglycerol and cholesterol, which was ascribable to blockage of beta-oxidation of fatty acids caused by decreased mRNA levels of the enzymes involved in the process, suppression of very-low-density lipoprotein formation due to destabilized apolipoprotein B-100, and stimulation of lipid droplet formation resulting from transcriptional induction of adipose differentiation-related protein. Accordingly, the hepatocytes of tunicamycin-injected knockout mice were filled with many lipid droplets. These results establish links among ER stress, lipid metabolism, and steatosis.


Assuntos
Fator 6 Ativador da Transcrição/deficiência , Retículo Endoplasmático/patologia , Fígado Gorduroso/genética , Metabolismo dos Lipídeos/genética , Estresse Fisiológico/efeitos dos fármacos , Tunicamicina/farmacologia , Fator 6 Ativador da Transcrição/genética , Fator 6 Ativador da Transcrição/metabolismo , Animais , Apolipoproteína B-100/metabolismo , Peso Corporal/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Fígado Gorduroso/patologia , Fígado Gorduroso/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Células Hep G2 , Humanos , Injeções Intraperitoneais , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/fisiopatologia , Fígado/ultraestrutura , Testes de Função Hepática , Camundongos , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Estresse Fisiológico/imunologia , Tunicamicina/administração & dosagem
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