RESUMO
BACKGROUND AND AIMS: Mitochondrial antiviral signaling protein (MAVS) is a critical regulator that activates the host's innate immunity against RNA viruses, and its signaling pathway has been linked to the secretion of proinflammatory cytokines. However, the actions of MAVS on inflammatory pathways during the development of metabolic dysfunction-associated steatotic liver disease (MASLD) have been little studied. APPROACH AND RESULTS: Liver proteomic analysis of mice with genetically manipulated hepatic p63, a transcription factor that induces liver steatosis, revealed MAVS as a target downstream of p63. MAVS was thus further evaluated in liver samples from patients and in animal models with MASLD. Genetic inhibition of MAVS was performed in hepatocyte cell lines, primary hepatocytes, spheroids, and mice. MAVS expression is induced in the liver of both animal models and people with MASLD as compared with those without liver disease. Using genetic knockdown of MAVS in adult mice ameliorates diet-induced MASLD. In vitro, silencing MAVS blunts oleic and palmitic acid-induced lipid content, while its overexpression increases the lipid load in hepatocytes. Inhibiting hepatic MAVS reduces circulating levels of the proinflammatory cytokine TNFα and the hepatic expression of both TNFα and NFκß. Moreover, the inhibition of ERK abolished the activation of TNFα induced by MAVS. The posttranslational modification O -GlcNAcylation of MAVS is required to activate inflammation and to promote the high lipid content in hepatocytes. CONCLUSIONS: MAVS is involved in the development of steatosis, and its inhibition in previously damaged hepatocytes can ameliorate MASLD.
RESUMO
OBJECTIVE: p63 is a transcription factor involved in multiple biological functions. In the liver, the TAp63 isoform induces lipid accumulation in hepatocytes. However, the role of liver TAp63 in the progression of metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis is unknown. METHODS: We evaluated the hepatic p63 levels in different mouse models of steatohepatitis with fibrosis induced by diet. Next, we used virogenetic approaches to manipulate the expression of TAp63 in adult mice under diet-induced steatohepatitis with fibrosis and characterized the disease condition. Finally, we performed proteomics analysis in mice with overexpression and knockdown of hepatic TAp63. RESULTS: Levels of TAp63, but not of ΔN isoform, are increased in the liver of mice with diet-induced steatohepatitis with fibrosis. Both preventive and interventional strategies for the knockdown of hepatic TAp63 significantly ameliorated diet-induced steatohepatitis with fibrosis in mice fed a methionine- and choline-deficient diet (MCDD) and choline deficient and high fat diet (CDHFD). The overexpression of hepatic TAp63 in mice aggravated the liver condition in mice fed a CDHFD. Proteomic analysis in the liver of these mice revealed alteration in multiple proteins and pathways, such as oxidative phosphorylation, antioxidant activity, peroxisome function and LDL clearance. CONCLUSIONS: These results indicate that liver TAp63 plays a critical role in the progression of diet-induced steatohepatitis with fibrosis, and its inhibition ameliorates the disease.
Assuntos
Fígado Gorduroso , Cirrose Hepática , Fígado , Camundongos Endogâmicos C57BL , Animais , Camundongos , Fígado/metabolismo , Fígado/patologia , Masculino , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Modelos Animais de Doenças , Dieta Hiperlipídica/efeitos adversos , Transativadores/metabolismo , Transativadores/genética , Proteômica , Metionina/deficiência , Metionina/metabolismoRESUMO
The p63 protein has pleiotropic functions and, in the liver, participates in the progression of nonalcoholic fatty liver disease (NAFLD). However, its functions in hepatic stellate cells (HSCs) have not yet been explored. TAp63 is induced in HSCs from animal models and patients with liver fibrosis and its levels positively correlate with NAFLD activity score and fibrosis stage. In mice, genetic depletion of TAp63 in HSCs reduces the diet-induced liver fibrosis. In vitro silencing of p63 blunts TGF-ß1-induced HSCs activation by reducing mitochondrial respiration and glycolysis, as well as decreasing acetyl CoA carboxylase 1 (ACC1). Ectopic expression of TAp63 induces the activation of HSCs and increases the expression and activity of ACC1 by promoting the transcriptional activity of HER2. Genetic inhibition of both HER2 and ACC1 blunt TAp63-induced activation of HSCs. Thus, TAp63 induces HSC activation by stimulating the HER2-ACC1 axis and participates in the development of liver fibrosis.
Assuntos
Células Estreladas do Fígado , Hepatopatia Gordurosa não Alcoólica , Humanos , Camundongos , Animais , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Ativação Metabólica , Cirrose Hepática/genética , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Fibrose , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismoRESUMO
A inscrição do feminino n'O Livro de Cabeceira enfoca as questões relativas à feminilidade através de uma análise do filme O Livro de Cabeceira (1995), de Peter Grennaway, inspirado no livro The Pillow Book, de autoria de Sei Sbonagon, cortesã japonesa do século XII. Nesse filme, bem ao estilo grennawayano, as associações de elementos aparentemente dissociados juntam-se em imagens emolduradas de corpos, letras e cores, em janelas simultâneas que evocam o passado a dispersar o presente de um espaço futuro. Veremos sexo e texto: eis a forma pela qual Peter Grennaway busca homenagear a escrita de Sei Shonagon, aquela que celebra o desfrute, o fruto descascado e mordido, os maiores prazeres da vida: os prazeres da carne e da literatura. As questões que emergem nesse filme nos levam ao encontro das diferentes construções da personagem Nagiko, como fio condutor de um processo de tessitura da inscrição do feminino ao longo das obras de Peter Greenaway, favorecendo interrogar as vias pelas quais as imagens do feminino, como real, insistem em tangenciar, em um processo contínuo, um apelo à sua inscrição nos insterstícios do tecido da linguagem(AU)