RNA helicase DEAD-box protein 5 alleviates nonalcoholic steatohepatitis progression via tethering TSC complex and suppressing mTORC1 signaling.
Hepatology
; 77(5): 1670-1687, 2023 05 01.
Article
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| MEDLINE
| ID: mdl-35796622
ABSTRACT
BACKGROUND AND AIMS:
Nonalcoholic fatty liver disease and its progressive form, nonalcoholic steatohepatitis (NASH), are rapidly becoming the top causes of hepatocellular carcinoma (HCC). Currently, there are no approved therapies for the treatment of NASH. DEAD-box protein 5 (DDX5) plays important roles in different cellular processes. However, the precise role of DDX5 in NASH remains unclear. APPROACH ANDRESULTS:
DDX5 expression was downregulated in patients with NASH, mouse models with diet-induced NASH (high-fat diet [HFD], methionine- and choline-deficient diet, and choline-deficient HFD), mouse models with NASH-HCC (diethylnitrosamine with HFD), and palmitic acid-stimulated hepatocytes. Adeno-associated virus-mediated DDX5 overexpression ameliorates hepatic steatosis and inflammation, whereas its deletion worsens such pathology. The untargeted metabolomics analysis was carried out to investigate the mechanism of DDX5 in NASH and NASH-HCC, which suggested the regulatory effect of DDX5 on lipid metabolism. DDX5 inhibits mechanistic target of rapamycin complex 1 (mTORC1) activation by recruiting the tuberous sclerosis complex (TSC)1/2 complex to mTORC1, thus improving lipid metabolism and attenuating the NACHT-, leucine-rich-repeat (LRR)-, and pyrin domain (PYD)-containing protein 3 inflammasome activation. We further identified that the phytochemical compound hyperforcinol K directly interacted with DDX5 and prevented its ubiquitinated degradation mediated by ubiquitin ligase (E3) tripartite motif protein 5, thereby significantly reducing lipid accumulation and inflammation in a NASH mouse model.CONCLUSIONS:
These findings provide mechanistic insight into the role of DDX5 in mTORC1 regulation and NASH progression, as well as suggest a number of targets and a promising lead compound for therapeutic interventions against NASH.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Carcinoma Hepatocelular
/
Enfermedad del Hígado Graso no Alcohólico
/
Neoplasias Hepáticas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Hepatology
Año:
2023
Tipo del documento:
Article
País de afiliación:
China