RESUMO
Interferon regulatory factors (IRFs) comprise a family of nine transcription factors in mammals. IRFs exert broad effects on almost all aspects of immunity but are best known for their role in the antiviral response. Over the past two decades, IRFs have been implicated in metabolic physiology and pathophysiology, partly as a result of their known functions in immune cells, but also because of direct actions in adipocytes, hepatocytes, myocytes and neurons. This Review focuses predominantly on IRF3 and IRF4, which have been the subject of the most intense investigation in this area. IRF3 is located in the cytosol and undergoes activation and nuclear translocation in response to various signals, including stimulation of Toll-like receptors, RIG-I-like receptors and the cGAS-STING pathways. IRF3 promotes weight gain, primarily by inhibiting adipose thermogenesis, and also induces inflammation and insulin resistance using both weight-dependent and weight-independent mechanisms. IRF4, meanwhile, is generally pro-thermogenic and anti-inflammatory and has profound effects on lipogenesis and lipolysis. Finally, new data are emerging on the role of other IRF family members in metabolic homeostasis. Taken together, data indicate that IRFs serve as critical yet underappreciated integrators of metabolic and inflammatory stress.
RESUMO
Metabolic stress due to nutrient excess and lipid accumulation is at the root of many age-associated disorders and the identification of therapeutic targets that mimic the beneficial effects of calorie restriction has clinical importance. Here, using C. elegans as a model organism, we study the roles of a recently discovered enzyme at the heart of metabolism in mammalian cells, glycerol-3-phosphate phosphatase (G3PP) (gene name Pgp) that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol. We identify three Pgp homologues in C. elegans (pgph) and demonstrate in vivo that their protein products have G3PP activity, essential for glycerol synthesis. We demonstrate that PGPH/G3PP regulates the adaptation to various stresses, in particular hyperosmolarity and glucotoxicity. Enhanced G3PP activity reduces fat accumulation, promotes healthy aging and acts as a calorie restriction mimetic at normal food intake without altering fertility. Thus, PGP/G3PP can be considered as a target for age-related metabolic disorders.
Assuntos
Adaptação Fisiológica/genética , Caenorhabditis elegans/genética , Glicerofosfatos/metabolismo , Proteínas de Helminto/genética , Longevidade/genética , Monoéster Fosfórico Hidrolases/genética , Sequência de Aminoácidos , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Restrição Calórica , Ingestão de Alimentos/genética , Regulação da Expressão Gênica , Glucose/metabolismo , Glucose/farmacologia , Glicerol/metabolismo , Glicerol-3-Fosfato O-Aciltransferase/genética , Glicerol-3-Fosfato O-Aciltransferase/metabolismo , Proteínas de Helminto/metabolismo , Isoenzimas/genética , Isoenzimas/metabolismo , Concentração Osmolar , Monoéster Fosfórico Hidrolases/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Estresse Fisiológico/genéticaRESUMO
Cytomegalovirus (CMV) infection is asymptomatic in the majority of immunocompetent patients. However, it can cause severe presentations, particularly in patients who are immunocompromised. We are reporting a rare association between respiratory failure secondary to cavitary pneumonia and a large pericardial effusion due to CMV infection in a patient with human immunodeficiency virus. The patient presented with hypoxic respiratory failure and a large pericardial effusion at risk of tamponade. After extensive investigation, the sole pathogen identified in the patient's bronchoalveolar lavage and pericardial fluid was CMV.
