Short-Term Statin Therapy Induces Hepatic Insulin Resistance Through HNF4α/PAQR9/PPM1α Axis Regulated AKT...

Area of Science:

• Biochemistry
• Endocrinology
• Molecular Biology

Background:

• Statins are primary treatments for dyslipidemia.
• Statins are associated with an increased risk of type 2 diabetes.
• The precise molecular mechanisms of statin-induced diabetes remain unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms by which statins induce hepatic insulin resistance and type 2 diabetes.
• To identify key molecular players and pathways involved in statin-induced diabetes.

Main Methods:

• Short-term statin therapy was administered to hyperlipidemia mouse models.
• Investigated the expression of progesterone and adiponectin receptor 9 (PAQR9) in the liver.
• Analyzed the interaction between PAQR9, protein phosphatase, Mg2+/Mn2+ dependent 1 (PPM1α), and STIP1 homology and U-box containing protein 1 (STUB1).
• Assessed the role of hepatocyte nuclear factor 4 alpha (HNF4α) in regulating PAQR9 expression.
• Evaluated the therapeutic potential of targeting the identified pathway.

Main Results:

• Statin therapy induced hepatic insulin resistance in mice.
• Statin medication increased hepatic PAQR9 expression, inhibiting insulin signaling via PPM1α degradation and ERK pathway activation.
• STUB1 was identified as a mediator of PAQR9-promoted PPM1α ubiquitination.
• Decreased HNF4α activity was linked to increased PAQR9 expression under statin treatment.
• Interventions targeting PAQR9, caloric restriction, HNF4α activation, and liver-specific PPM1α overexpression showed therapeutic effects.

Conclusions:

• The HNF4α-PAQR9-STUB1-PPM1α axis is crucial in mediating statin-induced hepatic insulin resistance.
• This study provides novel molecular insights into statin-induced diabetes.
• Targeting this axis presents potential therapeutic strategies for statin-induced diabetes.