Abstract
Mitochondrial 2-enoyl-acyl-carrier protein reductase (MECR) is an enzyme in the mitochondrial fatty acid synthase (mtFAS) pathway. MECR activity remains unknown in the mechanism of insulin resistance in the pathogenesis of type 2 diabetes. In the present study, MECR activity was investigated in diet-induced obese (DIO) mice. Mecr mRNA was induced by insulin in cell culture, and was elevated in the liver of DIO mice in the presence hyperinsulinemia. However, MECR protein was decreased in the liver of DIO mice, and the reduction was blocked by treatment of the DIO mice with berberine (BBR). The mechanism of MECR protein regulation was investigated with a focus on ATP. The protein was decreased in the cell lysate and DIO liver by an increase in ATP levels. The ATP protein reduction was blocked in the liver of BBR-treated mice by suppression of ATP elevation. The MECR protein reduction was associated with insulin resistance and the protein restoration was associated with improvement of insulin sensitivity by BBR in the DIO mice. The data suggest that MECR protein is regulated in hepatocytes by ATP in association with insulin resistance. The study provides evidence for a relationship between MECR protein and insulin resistance.
Highlights
Mitochondria provide intermediate metabolites to the glucose production pathway in hepatocytes in the maintenance of blood glucose by liver in the fasting conditions
We examined mRNA of Mecr in 3T3-L1 cells in response to several stimulations related to insulin resistance
The present study provides a new insight into the mechanism by which ATP induces insulin resistance
Summary
Mitochondria provide intermediate metabolites (such as acetyl-CoA) to the glucose production pathway (gluconeogenesis) in hepatocytes in the maintenance of blood glucose by liver in the fasting conditions. The gluconeogenesis is inhibited by insulin in the postprandial condition to attenuate the meal-induced hyperglycemia. The hepatocyte response to insulin is impaired in the insulin-resistant conditions leading to hyperglycemia, a pathological character of type 2 diabetes. Insulin resistance is a result of energy surplus [1], and ATP is a signal for the energy surplus [2]. Inhibition of ATP production by mitochondria is a mechanism for the diabetic medicine metformin in the improvement of insulin sensitivity [3]. ATP is believed to induce insulin resistance through a feedback regulation of mitochondrial function. The molecular target of ATP remains to be identified in mitochondria
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