Abstract
Free fatty acid (FFA)-induced pancreatic β-cell loss is implicated in the pathogenesis of type 2 diabetes mellitus (T2DM). It has been documented that circulating microRNA (miR)-802 levels are significantly greater in T2DM patients than in healthy subjects. However, the role of miR-802 in FFA-induced damage to β cells is still unclear. In the present study, we measured the expression of miR-802 in the INS-1 rat insulinoma cell line after palmitate treatment for 48 h. Gain- and loss-of-function studies were conducted to determine the function of miR-802 in palmitate-induced apoptosis and reactive oxygen species (ROS) production. The target gene(s) of miR-802 was functionally characterized. Compared to control cells, palmitate treatment caused a time- and concentration-dependent induction of miR-802 in INS-1 cells. Knockdown of miR-802 significantly blocked palmitate-induced apoptosis and attenuated ROS formation. Moreover, miR-802 downregulation prevented the reduction of prosurvival proteins Mcl-1 and Bcl-xL by palmitate. In contrast, ectopic expression of miR-802 stimulated apoptosis and ROS generation in INS-1 cells. Sirtuin 6 (SIRT6) was identified to be a direct target gene of miR-802. Overexpression of miR-802 suppressed the expression of SIRT6. Enforced expression of SIRT6 abolished the induction of apoptosis and ROS production by miR-802. Taken together, miR-802 is required for palmitate-induced damage to β cells by targeting SIRT6 and represents a potential therapeutic target for T2DM.