2500-PUB: Mir-302 Protects against Glucolipotoxicity-Induced ß-Cell Dysfunction and Apoptosis through the Regulation of MST1 and PDX1

Evidence is now revealed that the cytotoxic effect caused by elevated levels of plasma glucose and free fatty acids, also called as glucolipotoxicity, is particularly harmful for pancreatic β-cell. In fact, the mammalian Ste20-like kinase 1 (MST1) can mediate glucolipotoxicity-induced β-cell damages by degradation of pancreatic and duodenal homeobox 1 (PDX-1), which is known to play an essential role in maintaining β-cell function and survival. Interestingly, the activation of the pluripotency-related microRNA cluster miR-302 can protect β-cells from glucolipotoxicity-induced apoptosis. However, few studies have examined the related mechanism in detail. In the present study, we investigated the protective roles of miR-302 on rat pancreatic RINm5F β-cells, and demonstrated that MST1 was confirmed as a target of miR-302. As a result, the activation of miR-302restored the expression of PDX1 by inactivating MST1 thus ameliorating glucolipotoxicity-induced β-cell impairments. In addition, miR-302 also upregulated endogenous antioxidant signaling and autophagic activities during glucolipotoxicity, suggesting the anti-aging process may be also involved in miR-302-mediated protection.

In conclusion, our study suggests that miR-302 may serve as a potential target for developing new diagnoses and therapies to reduce glucolipotoxicity in β-cells.