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Dapansutrile Regulates Mitochondrial Oxidative Stress and Reduces Hepatic Lipid Accumulation in Diabetic Mice
1Department of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
Abstract:
(1) Background: Hepatic lipid accumulation is the initial factor in metabolic-associated fatty liver disease (MAFLD) in type 2 diabetics, leading to accelerated liver damage. The NOD-like receptor protein 3 (NLRP3) inflammasome plays a critical role in this process. Dapansutrile (DAPA) is a novel NLRP3 inflammasome inhibitor; however, its effect on ectopic lipid accumulation in the liver remains unclear. This study aimed to investigate the therapeutic effect of DAPA on hepatic lipid accumulation in a diabetic mouse model and its potential mechanisms. (2) Methods: The effects of DAPA on hepatic ectopic lipid deposition and liver function under metabolic stress were evaluated in vivo using db/db and high-fat diet (HFD) + streptozotocin (STZ) mouse models. Additionally, the role and mechanism of DAPA in cellular lipid deposition, mitochondrial oxidative stress, and inflammation were assessed in HepG2 cells treated with free fatty acids (FFA) and DAPA. (3) Results: Our findings indicated that DAPA treatment improved glucose and lipid metabolism in diabetic mice, particularly addressing liver heterotopic lipid deposition and insulin resistance. DAPA treatment also ameliorated lipid accumulation and mitochondrial-related functions and inflammation in HepG2 cells through the NLRP3-Caspase-1 signaling axis. (4) Conclusions: Targeting NLRP3 with DAPA may represent a novel therapeutic approach for diabetes-related fatty liver diseases.
Insights
Dapansutrile (DAPA), an NLRP3 inflammasome inhibitor, effectively reduced liver fat accumulation and improved metabolic health in diabetic mice. This suggests DAPA as a potential therapy for diabetes-related fatty liver disease.
Area of Science:
- Metabolic disorders
- Liver disease
- Inflammation
Background:
- Hepatic lipid accumulation initiates metabolic-associated fatty liver disease (MAFLD) in type 2 diabetes, exacerbating liver damage.
- The NOD-like receptor protein 3 (NLRP3) inflammasome is a key mediator in this pathological process.
- Dapansutrile (DAPA) is a novel NLRP3 inhibitor, but its impact on hepatic lipid accumulation is not well understood.
Purpose of the Study:
- To investigate the therapeutic potential of Dapansutrile (DAPA) in mitigating hepatic lipid accumulation.
- To elucidate the underlying mechanisms of DAPA's action in a diabetic mouse model and cellular systems.
Main Methods:
- Evaluated DAPA's effects on hepatic lipid deposition and liver function in db/db and high-fat diet (HFD) + streptozotocin (STZ) induced diabetic mouse models.
- Assessed DAPA's impact on cellular lipid deposition, mitochondrial function, and inflammation in HepG2 cells exposed to free fatty acids (FFA).
- Investigated the role of the NLRP3-Caspase-1 signaling pathway in DAPA's mechanism of action.
Main Results:
- DAPA treatment significantly improved glucose and lipid metabolism in diabetic mice, reducing ectopic liver fat deposition and insulin resistance.
- DAPA ameliorated lipid accumulation and improved mitochondrial function in HepG2 cells.
- DAPA demonstrated anti-inflammatory effects by modulating the NLRP3-Caspase-1 signaling axis in cellular models.
Conclusions:
- Targeting the NLRP3 inflammasome with Dapansutrile (DAPA) shows promise as a therapeutic strategy for managing fatty liver disease in diabetic patients.
- DAPA effectively reduces hepatic lipid accumulation and inflammation, offering a potential new treatment avenue for metabolic-associated fatty liver disease.
