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The deubiquitinase OTUB1 inhibits gluconeogenesis by stabilizing YWHAB

Qingwen Zhao1, Qianzhuo Wang2, Bei Li1

  • 1Zhejiang Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment of Senile Chronic Diseases, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Zhejiang 310006, China.

Cellular Signalling
|September 13, 2024
PubMed

Insights

The deubiquitinase OTU domain-containing ubiquitin aldehyde binding protein 1 (OTUB1) inhibits hepatic gluconeogenesis. Reduced OTUB1 worsens type 2 diabetes, while its restoration improves glucose homeostasis and insulin sensitivity.

Area of Science:

  • Biochemistry
  • Metabolism
  • Endocrinology

Background:

  • Hepatic gluconeogenesis is vital for glucose homeostasis and a target for type 2 diabetes treatment.
  • The precise molecular mechanisms regulating gluconeogenesis remain incompletely understood.

Purpose of the Study:

  • To investigate the role of OTU domain-containing ubiquitin aldehyde binding protein 1 (OTUB1) in regulating hepatic gluconeogenesis.
  • To explore OTUB1's potential as a therapeutic target for type 2 diabetes.

Main Methods:

  • Examined OTUB1 expression in db/db mice and type 2 diabetes patients.
  • Assessed the impact of hepatic OTUB1 deletion and overexpression on glucose metabolism.
  • Investigated the interaction between OTUB1 and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein β (YWHAB).

Main Results:

  • Hepatic OTUB1 expression was reduced in db/db mice and type 2 diabetes patients.
  • OTUB1 deletion elevated fasting blood glucose and key gluconeogenic gene expression.
  • OTUB1 overexpression in hepatocytes improved hyperglycemia and insulin sensitivity.
  • OTUB1 directly interacts with and deubiquitinates YWHAB, a known gluconeogenesis inhibitor.

Conclusions:

  • OTUB1 plays a critical role in suppressing hepatic gluconeogenesis.
  • OTUB1 deubiquitinates YWHAB, thereby inhibiting gluconeogenesis.
  • OTUB1 represents a promising therapeutic target for managing type 2 diabetes.
Keywords:
DeubiquitinationGluconeogenesisOTUB1YWHAB

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