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1.
Hepatology ; 67(3): 1071-1087, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-28960380

RESUMEN

It is urgent that the means to improve liver regeneration (LR) be found, while mitigating the concurrent risk of hepatocarcinogenesis (HCG). Nuclear receptor corepressor 1 (NCoR1) is a co-repressor of nuclear receptors, which regulates the expression level of metabolic genes; however, little is known about its potential contribution for LR and HCG. Here, we found that liver-specific NCoR1 knockout in mice (NCoR1Δhep ) dramatically enhances LR after partial hepatectomy and, surprisingly, blocks the process of diethylnitrosamine (DEN)-induced HCG. Both RNA-sequencing and metabolic assay results revealed improved expression of Fasn and Acc2 in NCoR1Δhep mice, suggesting the critical role of de novo fatty acid synthesis (FAS) in LR. Continual enhanced de novo FAS in NCoR1Δhep mice resulted in overwhelmed adenosine triphosphate ATP and nicotinamide adenine dinucleotide phosphate (NADPH) consumption and increased mitochondrial reactive oxygen species production, which subsequently attenuated HCG through inducing apoptosis of hepatocytes at an early stage after DEN administration. CONCLUSION: NCoR1 functions as a negative modulator for hepatic de novo FAS and mitochondria energy adaptation, playing distinct roles in regeneration or carcinogenesis. (Hepatology 2018;67:1071-1087).


Asunto(s)
Carcinogénesis/metabolismo , Lipogénesis/genética , Regeneración Hepática/genética , Hígado/metabolismo , Co-Represor 1 de Receptor Nuclear/metabolismo , Animales , Apoptosis , Proliferación Celular/genética , Ácidos Grasos/biosíntesis , Hepatocitos/metabolismo , Hígado/patología , Ratones , Ratones Noqueados
2.
J Virol ; 87(10): 5812-9, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23487465

RESUMEN

Viruses that replicate in the cytoplasm cannot access the host nuclear capping machinery. These viruses have evolved viral methyltransferase(s) to methylate N-7 and 2'-O cap of their RNA; alternatively, they "snatch" host mRNA cap to form the 5' end of viral RNA. The function of 2'-O methylation of viral RNA cap is to mimic cellular mRNA and to evade host innate immune restriction. A cytoplasmic virus defective in 2'-O methylation is replicative, but its viral RNA lacks 2'-O methylation and is recognized and eliminated by the host immune response. Such a mutant virus could be rationally designed as a live attenuated vaccine. Here, we use Japanese encephalitis virus (JEV), an important mosquito-borne flavivirus, to prove this novel vaccine concept. We show that JEV methyltransferase is responsible for both N-7 and 2'-O cap methylations as well as evasion of host innate immune response. Recombinant virus completely defective in 2'-O methylation was stable in cell culture after being passaged for >30 days. The mutant virus was attenuated in mice, elicited robust humoral and cellular immune responses, and retained the engineered mutation in vivo. A single dose of immunization induced full protection against lethal challenge with JEV strains in mice. Mechanistically, the attenuation phenotype was attributed to the enhanced sensitivity of the mutant virus to the antiviral effects of interferon and IFIT proteins. Collectively, the results demonstrate the feasibility of using 2'-O methylation-defective virus as a vaccine approach; this vaccine approach should be applicable to other flaviviruses and nonflaviviruses that encode their own viral 2'-O methyltransferases.


Asunto(s)
Virus de la Encefalitis Japonesa (Especie)/enzimología , Virus de la Encefalitis Japonesa (Especie)/genética , Encefalitis Japonesa/prevención & control , Vacunas contra la Encefalitis Japonesa/genética , Vacunas contra la Encefalitis Japonesa/inmunología , ARN Viral/metabolismo , ARNt Metiltransferasas/deficiencia , Animales , Anticuerpos Antivirales/sangre , Modelos Animales de Enfermedad , Virus de la Encefalitis Japonesa (Especie)/patogenicidad , Encefalitis Japonesa/patología , Encefalitis Japonesa/virología , Femenino , Vacunas contra la Encefalitis Japonesa/administración & dosificación , Leucocitos Mononucleares/inmunología , Metilación , Ratones , Ratones Endogámicos BALB C , Análisis de Supervivencia , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/genética , Vacunas Atenuadas/inmunología
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