Decreased carboxylesterases expression and hydrolytic activity in type 2 diabetic mice through Akt/mTOR/HIF-1α/Stra13...

Area of Science:

• Biochemistry
• Metabolic Diseases
• Molecular Biology

Background:

• Carboxylesterases (CES) play crucial roles in drug and xenobiotic metabolism.
• Alterations in CES activity are implicated in various metabolic disorders, including type 2 diabetes (T2D).
• The molecular mechanisms underlying CES dysregulation in T2D remain incompletely understood.

Purpose of the Study:

• To investigate the impact of type 2 diabetes on carboxylesterase expression and activity.
• To elucidate the signaling pathways involved in CES alterations in T2D.
• To explore potential therapeutic targets for managing CES dysfunction in T2D.

Main Methods:

• Comparative analysis of CES1d and CES1e expression and hydrolytic activity in T2D mice versus control groups.
• In vitro studies using primary mouse hepatocytes and human hepatoma (HepG2) cells exposed to high glucose and insulin conditions mimicking T2D.
• Pharmacological inhibition of Akt/mTOR pathway (Perifosine, Rapamycin) and genetic knockdown of HIF-1α and DEC1 (Stra13) using shRNA constructs.

Main Results:

• T2D mice exhibited decreased CES1d and CES1e expression and hydrolytic activity in the liver and intestine.
• High insulin and glucose conditions in vitro replicated the reduced CES expression and activity observed in T2D mice.
• Inhibition of the Akt/mTOR pathway and knockdown of HIF-1α or DEC1 significantly restored CES expression and activity.
• HepG2 cells showed similar responsiveness to high insulin/glucose conditions as primary hepatocytes.

Conclusions:

• The Akt/mTOR/HIF-1α/DEC1 signaling pathway is a key mediator of decreased carboxylesterase expression and hydrolytic activity in type 2 diabetes.
• Targeting this pathway may offer a therapeutic strategy to normalize CES function in T2D.
• Understanding these molecular mechanisms provides insights into the metabolic dysregulation associated with T2D.