Antioxidant Signaling Involving the Microtubule Motor KIF12 Is an Intracellular Target of Nutrition Excess in Beta Cells

Abstract

Beta cell injury due to oxidative stress is a typical etiology of diabetes caused by nutritional excess, but its precise mechanism remains largely elusive. Here, we demonstrate that the microtubule motor KIF12 mediates an antioxidant cascade in beta cells as an intracellular target of excess fat intake or "lipotoxicity." KIF12 knockout mice suffer from hypoinsulinemic glucose intolerance due to increased beta cell oxidative stress. Using this model, we identified an antioxidant signaling cascade involving KIF12 as a scaffold for the transcription factor Sp1.The stabilization of nascent Sp1 appeared to be essential for proper peroxisomal function by enhancing Hsc70 expression, and the pharmacological induction of Hsc70 expression with teprenone counteracted the oxidative stress. Because KIF12 is transcriptionally downregulated by chronic exposure to fatty acids, this antioxidant cascade involving KIF12 and Hsc70 is proposed to be a critical target of nutritional excess in beta cells in diabetes.