Chronic Hyperinsulinemia Causes Selective Insulin Resistance and Down-regulates Uncoupling Protein 3 (UCP3) through the Activation of Sterol Regulatory Element-binding Protein (SREBP)-1 Transcription Factor in the Mouse Heart

The risk for heart failure and death after myocardial infarction is abnormally high in diabetic subjects. We and others have shown previously that mitochondrial uncoupling protein 3 (UCP3) improves functional recovery of the rodent heart during reperfusion. Here, we demonstrate that pharmacological induction of hyperinsulinemia in mice down-regulates myocardial UCP3. Decreased UCP3 expression was linked to the development of selective insulin resistance in the heart, characterized by decreased basal activity of Akt but preserved activity of the p44/42 mitogen-activated protein kinase, and overactivation of the sterol regulatory element-binding protein (SREBP)-1-mediated lipogenic program. In cultured myocytes, insulin treatment and SREBP-1 overexpression decreased, whereas SREBP-1 interference increased, peroxisome proliferator-activated receptor-stimulated expression of UCP3. Promoter deletion and site-directed mutagenesis identified three functional sterol regulatory elements in the vicinity of a known complex intronic enhancer. Increased binding of SREBP-1 to this DNA region was confirmed in the heart of hyperinsulinemic mice. In conclusion, we describe a hitherto unknown regulatory mechanism by which insulin inhibits cardiac UCP3 expression through activation of the lipogenic factor SREBP-1. Sustained down-regulation of cardiac UCP3 by hyperinsulinemia may partly explain the poor prognosis of type 2 diabetic patients after myocardial infarction.