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Canagliflozin ameliorates the development of NAFLD by preventing NLRP3-mediated pyroptosis through FGF21-ERK1/2
Shaohan Huang1, Beibei Wu1, Yingzi He1
1Department of Endocrinology, The Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
Abstract:
Recent studies have suggested that sodium-glucose co-transporter2 inhibitors go beyond their glycemic advantages to ameliorate the development of NAFLD. However, little research has been done on the underlying mechanisms. Here, we took deep insight into the effect of canagliflozin (CANA), one of the sodium-glucose co-transporter2 inhibitor, on the progression of NAFLD, and explored the molecular mechanisms. Our findings showed that CANA-treated ob/ob and diabetic mice developed improved glucose and insulin tolerance, although their body weights were comparable or even increased compared with the controls. The CANA treatment ameliorated hepatic steatosis and lipid accumulation of free fatty acid-treated AML12 cells, accompanied by decreased lipogenic gene expression and increased fatty acid β oxidation-related gene expression. Furthermore, inflammation and fibrosis genes decreased in the livers of CANA-treated ob/ob and diabetic mice mice. FGF21 and its downstream ERK1/2/AMPK signaling decreased, whereas NLRP3-mediated pyroptosis increased in the livers of the ob/ob and diabetic mice mice, which was reversed by the CANA treatment. In addition, blocking FGF21 or ERK1/2 activity antagonized the effects of CANA on NLRP3-mediated pyroptosis in lipopolysaccharide plus nigericin-treated J774A.1 cells. We conclude that CANA treatment alleviated insulin resistance and the progression of NAFLD in ob/ob and diabetic mice mice independent of the body weight change. CANA protected against the progression of NAFLD by inhibiting NLRP3-mediated pyroptosis and enhancing FGF21-ERK1/2 pathway activity in the liver. These findings suggest the therapeutic potential of sodium-glucose co-transporter2 inhibitors in the treatment of NAFLD.
Insights
Sodium-glucose co-transporter2 inhibitors, like canagliflozin, show promise in treating non-alcoholic fatty liver disease (NAFLD). Canagliflozin improves insulin resistance and liver health by reducing inflammation and pyroptosis, independent of weight changes.
Area of Science:
- Metabolism and Endocrinology
- Hepatology
- Pharmacology
Background:
- Sodium-glucose co-transporter2 inhibitors (SGLT2i) offer benefits beyond glycemic control, with emerging evidence suggesting efficacy in non-alcoholic fatty liver disease (NAFLD).
- The precise molecular mechanisms underlying SGLT2i's effects on NAFLD progression remain incompletely understood.
Purpose of the Study:
- To investigate the impact of canagliflozin (CANA), an SGLT2i, on NAFLD progression in preclinical models.
- To elucidate the underlying molecular pathways involved in canagliflozin's therapeutic effects on NAFLD.
Main Methods:
- Utilized ob/ob and diabetic mouse models, alongside AML12 and J774A.1 cell lines, to assess canagliflozin's effects.
- Analyzed glucose/insulin tolerance, hepatic steatosis, lipid accumulation, gene expression (lipogenesis, fatty acid oxidation, inflammation, fibrosis), and key signaling pathways (FGF21, ERK1/2, AMPK, NLRP3 inflammasome).
Main Results:
- Canagliflozin improved glucose and insulin tolerance in mice, ameliorated hepatic steatosis and lipid accumulation in cells, and reduced lipogenic gene expression while increasing fatty acid oxidation.
- Canagliflozin decreased hepatic inflammation and fibrosis markers, and importantly, reversed the downregulation of FGF21-ERK1/2 signaling and the upregulation of NLRP3-mediated pyroptosis observed in disease models.
- Inhibition of FGF21 or ERK1/2 activity counteracted canagliflozin's protective effects on pyroptosis.
Conclusions:
- Canagliflozin effectively alleviates insulin resistance and NAFLD progression in preclinical models, irrespective of body weight changes.
- Canagliflozin exerts its protective effects against NAFLD by inhibiting NLRP3-mediated pyroptosis and concurrently enhancing hepatic FGF21-ERK1/2 pathway activity.
- SGLT2 inhibitors represent a potential therapeutic strategy for managing NAFLD.
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