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1.
Int J Mol Sci ; 19(10)2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30261697

RESUMO

Among multiple distinct isoforms, Nrf1D is synthesized from a de novo translation of an alternatively-spliced transcript of Nrf1 mRNA, as accompanied by a naturally-occurring deletion of its stop codon-flanking 1466 nucleotides. This molecular event leads to the generation of a reading frameshift mutation, which results in a constitutive substitution of the intact Nrf1's C-terminal 72 amino acids (aa, covering the second half of the leucine zipper motif to C-terminal Neh3L domain) by an additional extended 80-aa stretch to generate a unique variant Nrf1D. The C-terminal extra 80-aa region of Nrf1D was herein identified to be folded into a redox-sensitive transmembrane domain, enabling it to be tightly integrated within the endoplasmic reticulum (ER) membranes. Notably, the salient feature of Nrf1D enables it to be distinguishable from prototypic Nrf1, such that Nrf1D is endowed with a lesser ability than wild-type Nrf1 to mediate target gene expression. Further evidence has also been presented revealing that both mRNA and protein levels of Nrf1D, together with other isoforms similar to those of Nrf1, were detected to varying extents in hemopoietic and somatic tissues. Surprisingly, we found the existence of Nrf1D-derived isoforms in blood plasma, implying that it is a candidate secretory transcription factor, albeit its precursor acts as an integral transmembrane-bound CNC-bZIP protein that entails dynamic topologies across membranes, before being unleashed from the ER to enter the blood.


Assuntos
Células da Medula Óssea/metabolismo , Fator 1 Nuclear Respiratório/metabolismo , Estresse Oxidativo , Precursores de Proteínas/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/química , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Encéfalo/metabolismo , Células COS , Chlorocebus aethiops , Feminino , Células Hep G2 , Humanos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator 1 Nuclear Respiratório/sangue , Fator 1 Nuclear Respiratório/química , Fator 1 Nuclear Respiratório/genética , Domínios Proteicos , Precursores de Proteínas/química , Precursores de Proteínas/genética , Pele/metabolismo , Testículo/metabolismo
2.
Biol Pharm Bull ; 40(3): 339-344, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28250276

RESUMO

Targeting energy expenditure provides a potential alternative strategy for achieving energy balance to combat obesity and the development of type 2 diabetes mellitus (T2DM). In the present study, we investigated whether atractylenolide III (AIII) regulates energy metabolism in skeletal muscle cells. Differentiated C2C12 myotubes were treated with AIII (10, 20, or 50 µM) or metformin (2.5 mM) for indicated times. The levels of glucose uptake, the expressions of key mitochondrial biogenesis-related factors and their target genes were measured in C2C12 myotubes. AIII significantly increased the glucose uptake levels, and significantly increased the expressions of peroxisome proliferator-activated receptor coactivator-1α (PGC1α) and mitochondrial biogenesis-related markers, such as, nuclear respiratory factor-1 (NRF-1), and mitochondrial transcription factor A (TFAM) and mitochondrial mass and total ATP contents. In addition, AIII significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of sirtuin1 (SIRT1). These results suggest that AIII may have beneficial effects on obesity and T2DM by improving energy metabolism in skeletal muscle.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Metabolismo Energético/efeitos dos fármacos , Lactonas/farmacologia , Músculo Esquelético/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Extratos Vegetais/farmacologia , Sesquiterpenos/farmacologia , Sirtuína 1/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Atractylodes/química , Glicemia/metabolismo , Linhagem Celular , Proteínas de Ligação a DNA/sangue , Diabetes Mellitus Tipo 2/metabolismo , Proteínas de Grupo de Alta Mobilidade/sangue , Camundongos , Mitocôndrias/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Fator 1 Nuclear Respiratório/sangue , Obesidade/metabolismo , Fosforilação
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