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Glucocorticoid treatment alters systemic bile acid homeostasis by regulating the biosynthesis and transport of bile salts.
Digestive and Liver Disease 2016 July
BACKGROUND: Dysregulation of systemic bile acid homeostasis can lead to cholestatic liver diseases and metabolic syndromes. As important anti-inflammatory and immunosuppressive drugs, synthetic glucocorticoids (GCs) are used to treat several cholestatic disorders, including biliary atresia (BA), because of their effects on the regulation of bile acid metabolism. However, the molecular mechanisms that underlie GCs regulation of bile acid homeostasis remain unclear.
AIMS: To provide a mechanistic basis for the effects of GCs on bile acid homeostasis.
METHODS: Male rats were treated with methylprednisolone for 7 days with slow-release osmotic pumps under physiological and cholestatic status that was induced by bile duct ligation (BDL). Expression of glucocorticoid receptor (GR) and genes related to bile acid metabolism was investigated using western blotting, qRT-PCR and immunohistochemistry.
RESULTS: We show here that sustained treatment with GCs in rats disrupts the normal changes in systemic bile acid distribution by elevating plasma bile acid levels and reducing faecal bile acid loss. Treatment with GCs stimulated bile acid absorption in the ileum by increasing expression of the apical sodium-dependent bile acid transporter (Asbt). Concomitantly, administration of GCs enhanced liver bile acid uptake by increasing the expression of the major hepatocyte basolateral bile transporter (Ntcp). The reduced expression of a bile acid synthesis rate-controlling enzyme, Cyp7a1, suggests that treatment with GCs suppressed hepatic bile acid synthesis.
CONCLUSION: Our study provides evidence that GCs can increase enterohepatic bile acid circulation through regulation of the biosynthesis and transport of bile salts, which suggests that plasma bile acid levels should be monitored during treatment with GCs in patients with BA.
AIMS: To provide a mechanistic basis for the effects of GCs on bile acid homeostasis.
METHODS: Male rats were treated with methylprednisolone for 7 days with slow-release osmotic pumps under physiological and cholestatic status that was induced by bile duct ligation (BDL). Expression of glucocorticoid receptor (GR) and genes related to bile acid metabolism was investigated using western blotting, qRT-PCR and immunohistochemistry.
RESULTS: We show here that sustained treatment with GCs in rats disrupts the normal changes in systemic bile acid distribution by elevating plasma bile acid levels and reducing faecal bile acid loss. Treatment with GCs stimulated bile acid absorption in the ileum by increasing expression of the apical sodium-dependent bile acid transporter (Asbt). Concomitantly, administration of GCs enhanced liver bile acid uptake by increasing the expression of the major hepatocyte basolateral bile transporter (Ntcp). The reduced expression of a bile acid synthesis rate-controlling enzyme, Cyp7a1, suggests that treatment with GCs suppressed hepatic bile acid synthesis.
CONCLUSION: Our study provides evidence that GCs can increase enterohepatic bile acid circulation through regulation of the biosynthesis and transport of bile salts, which suggests that plasma bile acid levels should be monitored during treatment with GCs in patients with BA.
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