Transcription Factor HMG Box-Containing Protein 1 (HBP1) Regulates Glycemic Homeostasis Through Modulation of Gluconeogenesis

Abstract

Abstract Objectives Glycemic dysregulation is one of the major metabolic disorders, which has long been a significant public health issue. The liver plays a pivotal role in the maintenance of blood glucose homeostasis. Previous studies indicate that upon refeeding a high carbohydrate diet, the expression of transcription factor HMG box-containing protein 1 (HBP1) was elevated in mice livers, suggesting a role of HBP1 in carbohydrate metabolism. Therefore, the objective of the current study was to understand the molecular mechanisms through which HBP1 regulates glucose generation in the liver. Methods Both in vivo HBP1 knockdown mice and in vitro HepG2 cell line were employed as the experimental models. Results First, we observed that overnight fasting led to increased PEPCK but decreased HBP1 expression in mice livers, and subsequent addition of insulin reversed the expression pattern. More importantly, HBP1 knockout (KO) mice displayed a significantly higher blood glucose level (173 mg/dL) than that of the controls (98 mg/dL). Also, HBP1 KO led to impaired OGTT (oral glucose tolerance test) and ITT (insulin tolerance test). These data suggest that HBP1 might have a role in the regulation of gluconeogenesis in the liver. To unveil the molecular mechanism by which HBP1 regulates glucose homeostasis, we examined its role in gluconeogenesis. Administration of gluconeogenic stimulators glucagon (100 nM) and cAMP (0.5 ng/mL) resulted in increased expression of Phosphoenolpyruvate carboxykinase (PEPCK; encoded by the PCK1 gene), a key enzyme in gluconeogenesis, but decreased HBP1 expression in HepG2 cells. Last, HBP1 siRNA-mediated mRNA disruption led to elevated PEPCK expression, whereas ectopic expression of HBP1 (pcDNA3-HBP1-Flag) significantly suppressed it. Conclusions In conclusion, our data indicate that HBP1 might negatively regulate glucose production and support HBP1 as a novel biological regulator of blood glucose homeostasis. Funding Sources This work was supported by the grant to MOST 108–2320-B-039–051-MY3 C-Y Huang.