AGER1 downregulation associates with fibrosis in nonalcoholic steatohepatitis and type 2 diabetes.
J Clin Invest
; 130(8): 4320-4330, 2020 08 03.
Article
en En
| MEDLINE
| ID: mdl-32657776
ABSTRACT
Type 2 diabetes is clinically associated with progressive necroinflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Advanced glycation end-products (AGEs) accumulate during prolonged hyperglycemia, but the mechanistic pathways that lead to accelerated liver fibrosis have not been well defined. In this study, we show that the AGEs clearance receptor AGER1 was downregulated in patients with NASH and diabetes and in our NASH models, whereas the proinflammatory receptor RAGE was induced. These findings were associated with necroinflammatory, fibrogenic, and pro-oxidant activity via the NADPH oxidase 4. Inhibition of AGEs or RAGE deletion in hepatocytes in vivo reversed these effects. We demonstrate that dysregulation of NRF2 by neddylation of cullin 3 was linked to AGER1 downregulation and that induction of NRF2 using an adeno-associated virus-mediated approach in hepatocytes in vivo reversed AGER1 downregulation, lowered the level of AGEs, and improved proinflammatory and fibrogenic responses in mice on a high AGEs diet. In patients with NASH and diabetes or insulin resistance, low AGER1 levels were associated with hepatocyte ballooning degeneration and ductular reaction. Collectively, prolonged exposure to AGEs in the liver promotes an AGER1/RAGE imbalance and consequent redox, inflammatory, and fibrogenic activity in NASH.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Regulación hacia Abajo
/
Diabetes Mellitus Tipo 2
/
Enfermedad del Hígado Graso no Alcohólico
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Receptor para Productos Finales de Glicación Avanzada
/
Cirrosis Hepática
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
J Clin Invest
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos