Identification of the functions of human ANGPTL6 in metabolic syndrome
Dept. of Medicine/박사
Although adipocentric view is currently regarded as a common pathogenesis of metabolic syndrome, the ultimate cause of metabolic syndrome is excessive energy status. Just like the adipose tissue, the liver has been redefined as an endocrine organ. One of the novel hepatokines, ANGPTL6, showed therapeutic potential against diabetes and obesity in animal model as it increases energy expenditure, decreases gluconeogeneis, and improves lipid and sugar profiles. However, human studies demonstrated paradoxically increased serum ANGPTL6 level in preeclampsia and diabetes. In this study, serum levels of ANGPTL6 were analyzed in Korean persons. The analysis showed that serum ANGPTL6 level was significantly higher in subjects with metabolic syndrome than those in the healthy group (p-value<0.001), and also higher in females than in males (p-value<0.05). Among the components of metabolic syndrome, subjects with decreased high-density lipoprotein cholesterol had significantly increased serum ANGPTL6 (p-value<0.05). Female, young age, metabolic syndrome itself and waist circumference could be used as independent predictors of serum ANGPTL6 level (p-value<0.05). To identify the functions of human ANGPTL6, expressional profiling was performed with ANGPTL6-transfected human hepatoma cell HUH7. Among the targets of rate-limiting or key enzymes of metabolism, expression of glucose-6-phosphatase was decreased by ANGPTL6 transfection and increased by ANGPTL6 siRNA transfection (p-value<0.05). With computational prediction, several nuclear receptor response elements were discovered in the promoter region of ANGPTL6. In vitro assay showed increased ANGPTL6 expression after treatments with FXR or LXR agonists. In conclusion, human ANGPTL6, which decreases gluconeogenesis in human hepatoma cell, seems to be compensatory up-regulated or resistant status in metabolic syndrome. Since the expression of ANGPTL6 can be up-regulated by nuclear receptor agonists, it is thought ANGPTL6 has therapeutic potential against metabolic syndrome in human.