title: Inhibition of gluconeogenic genes by calcium-regulated heat-stable protein 1 via repression of peroxisome proliferator-activated receptor α.
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.
authors: Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
authors: Yanbo
authors: Y
authors: Fan
authors: Yanhong
authors: Y
authors: Guo
authors: Milton
authors: M
authors: Hamblin
authors: Lin
authors: L
authors: Chang
authors: Jifeng
authors: J
authors: Zhang
authors: Y Eugene
authors: YE
authors: Chen
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D005943:Gluconeogenesis / Q000235:genetics*; D005952:Glucose-6-Phosphatase / Q000737:chemistry / Q000235:genetics; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D010730:Phosphoenolpyruvate Carboxylase / Q000235:genetics; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C114342:CARHSP1 protein, human; D004268:DNA-Binding Proteins; D047493:PPAR alpha; D010750:Phosphoproteins; D014157:Transcription Factors; D005952:Glucose-6-Phosphatase; D010730:Phosphoenolpyruvate Carboxylase