Abstract
Gluconeogenesis contributes to insulin resistance in type 1 and type 2 diabetes, but its regulation and the underlying molecular mechanisms remain unclear. Recently, calcium-regulated heat-stable protein 1 (CARHSP1) was identified as a biomarker for diabetic complications. In this study, we investigated the role of CARHSP1 in hepatic gluconeogenesis. We assessed the regulation of hepatic CARHSP1 expression under conditions of fasting and refeeding. Adenovirus-mediated CARHSP1 overexpression and siRNA-mediated knockdown experiments were performed to characterize the role of CARHSP1 in the regulation of gluconeogenic gene expression. Here, we document for the first time that CARHSP1 is regulated by nutrient status in the liver and functions at the transcriptional level to negatively regulate gluconeogenic genes, including the glucose-6-phosphatase catalytic subunit (G6Pc) and phosphoenolpyruvate carboxykinase 1 (PEPCK1). In addition, we found that CARHSP1 can physically interact with peroxisome proliferator-activated receptor-α (PPARα) and inhibit its transcriptional activity. Both pharmacological and genetic ablations of PPARα attenuate the inhibitory effect of CARHSP1 on gluconeogenic gene expression in hepatocytes. Our data suggest that CARHSP1 inhibits hepatic gluconeogenic gene expression via repression of PPARα and that CARHSP1 may be a molecular target for the treatment of diabetes.
Highlights
Gluconeogenesis contributes to insulin resistance in type 1 and type 2 diabetes, but underlying molecular mechanisms remain unclear
calcium-regulated heat-stable protein 1 (CARHSP1) mRNA expression was down-regulated, whereas glucose-6-phosphatase catalytic subunit (G6Pc) and phosphoenolpyruvate carboxykinase 1 (PEPCK1) mRNA levels were up-regulated by stimulation with forskolin and dexamethasone (Fig. 1E)
G6Pc and PEPCK1 are regulated at the transcriptional level by a variety of hormonal and nutrient signals including insulin, glucocorticoids, thyroid hormones, and cyclic AMP (15, 16)
Summary
Gluconeogenesis contributes to insulin resistance in type 1 and type 2 diabetes, but underlying molecular mechanisms remain unclear. Conclusion: CARHSP1 inhibits hepatic gluconeogenic gene expression via repression of PPAR␣. Gluconeogenesis contributes to insulin resistance in type 1 and type 2 diabetes, but its regulation and the underlying molecular mechanisms remain unclear. We document for the first time that CARHSP1 is regulated by nutrient status in the liver and functions at the transcriptional level to negatively regulate gluconeogenic genes, including the glucose-6-phosphatase catalytic subunit (G6Pc) and phosphoenolpyruvate carboxykinase 1 (PEPCK1). Our data suggest that CARHSP1 inhibits hepatic gluconeogenic gene expression via repression of PPAR␣ and that CARHSP1 may be a molecular target for the treatment of diabetes. Gluconeogenesis is controlled by certain rate-limiting enzymes such as the glucose-6-phosphatase catalytic subunit (G6Pc) and phosphoenolpyruvate carboxykinase (PEPCK), and these genes are regulated by critical metabolism-related hormones including insulin, glucagon, and glucocorticoids. We demonstrate that CARHSP1 can potently inhibit the expression of gluconeogenic genes, including G6Pc and PEPCK1, when overexpressed in
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