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RNA helicase DEAD-box protein 5 alleviates nonalcoholic steatohepatitis progression via tethering TSC complex and

Yanqiu Zhang1, Shengtao Ye, Weijia Lu

  • 1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines , School of Traditional Chinese Pharmacy , China Pharmaceutical University , Nanjing , China.

Hepatology (Baltimore, Md.)
|July 7, 2022
PubMed
Abstract

Insights

DEAD-box protein 5 (DDX5) is downregulated in nonalcoholic steatohepatitis (NASH). Restoring DDX5 ameliorates NASH by inhibiting mTORC1 activation and inflammasome activity, suggesting DDX5 as a therapeutic target.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Oncology

Background:

  • Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are leading causes of hepatocellular carcinoma (HCC).
  • Current therapeutic options for NASH are limited.
  • The role of DEAD-box protein 5 (DDX5) in NASH pathogenesis is not well understood.

Purpose of the Study:

  • To elucidate the role of DDX5 in the mechanisms underlying NASH and NASH-associated HCC.
  • To investigate DDX5's potential as a therapeutic target for NASH.

Main Methods:

  • Analysis of DDX5 expression in human NASH patients and various mouse models of NASH and NASH-HCC.
  • Investigated the effects of DDX5 modulation (overexpression and deletion) on hepatic steatosis and inflammation.
  • Utilized untargeted metabolomics and identified molecular interactions to understand DDX5's mechanism of action.
  • Assessed the therapeutic potential of hyperforin K, a phytochemical compound targeting DDX5.

Main Results:

  • DDX5 expression was significantly downregulated in NASH patients, NASH mouse models, and hepatocytes exposed to palmitic acid.
  • DDX5 overexpression ameliorated hepatic steatosis and inflammation, while DDX5 deletion exacerbated these conditions.
  • DDX5 inhibits mechanistic target of rapamycin complex 1 (mTORC1) activation by recruiting the tuberous sclerosis complex (TSC)1/2 complex, improving lipid metabolism and reducing inflammasome activation.
  • The phytochemical hyperforin K directly interacted with DDX5, preventing its degradation and reducing lipid accumulation and inflammation in a NASH mouse model.

Conclusions:

  • DDX5 plays a critical role in regulating mTORC1 signaling and mitigating NASH progression.
  • These findings reveal DDX5 as a key regulator of lipid metabolism and inflammation in NASH.
  • DDX5 and its regulators, such as hyperforin K, represent promising therapeutic targets for NASH intervention.

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