Asunto(s)
Anticuerpos Neutralizantes , Terapia Genética , Animales , Primates , Proyectos de InvestigaciónRESUMEN
This corrects the article DOI: 10.1038/nm.4290.
RESUMEN
Non-alcoholic steatohepatitis (NASH) is an increasingly prevalent liver pathology that can progress from non-alcoholic fatty liver disease (NAFLD), and it is a leading cause of cirrhosis and hepatocellular carcinoma. There is currently no pharmacological therapy for NASH. Defective lysosome-mediated protein degradation is a key process that underlies steatohepatitis and a well-recognized drug target in a variety of diseases; however, whether it can serve as a therapeutic target for NAFLD and NASH remains unknown. Here we report that transmembrane BAX inhibitor motif-containing 1 (TMBIM1) is an effective suppressor of steatohepatitis and a previously unknown regulator of the multivesicular body (MVB)-lysosomal pathway. Tmbim1 expression in hepatocytes substantially inhibited high-fat diet-induced insulin resistance, hepatic steatosis and inflammation in mice. Mechanistically, Tmbim1 promoted the lysosomal degradation of toll-like receptor 4 by cooperating with the ESCRT endosomal sorting complex to facilitate MVB formation, and the ubiquitination of Tmbim1 by the E3 ubiquitin ligase Nedd4l was required for this process. We also found that overexpression of Tmbim1 in the liver effectively inhibited a severe form of NAFLD in mice and NASH progression in monkeys. Taken together, these findings could lead to the development of promising strategies to treat NASH by targeting MVB regulators to properly orchestrate the lysosome-mediated protein degradation of key mediators of the disease.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas de la Membrana/metabolismo , Cuerpos Multivesiculares/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptor Toll-Like 4/metabolismo , Adolescente , Adulto , Animales , Western Blotting , Citocinas/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Células HEK293 , Células HeLa , Humanos , Inmunohistoquímica , Lisosomas/metabolismo , Macaca fascicularis , Masculino , Ratones , Ratones Noqueados , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Ubiquitina-Proteína Ligasas Nedd4 , Reacción en Cadena de la Polimerasa , Tomografía de Emisión de Positrones , Células RAW 264.7 , Ubiquitina-Proteína Ligasas/metabolismo , Adulto JovenRESUMEN
Nonalcoholic steatohepatitis (NASH) is a progressive disease that is often accompanied by metabolic syndrome and poses a high risk of severe liver damage. However, no effective pharmacological treatment is currently available for NASH. Here we report that CASP8 and FADD-like apoptosis regulator (CFLAR) is a key suppressor of steatohepatitis and its metabolic disorders. We provide mechanistic evidence that CFLAR directly targets the kinase MAP3K5 (also known as ASK1) and interrupts its N-terminus-mediated dimerization, thereby blocking signaling involving ASK1 and the kinase MAPK8 (also known as JNK1). Furthermore, we identified a small peptide segment in CFLAR that effectively attenuates the progression of steatohepatitis and metabolic disorders in both mice and monkeys by disrupting the N-terminus-mediated dimerization of ASK1 when the peptide is expressed from an injected adenovirus-associated virus 8-based vector. Taken together, these findings establish CFLAR as a key suppressor of steatohepatitis and indicate that the development of CFLAR-peptide-mimicking drugs and the screening of small-molecular inhibitors that specifically block ASK1 dimerization are new and feasible approaches for NASH treatment.