Abstract
To investigate the mechanism of 25 hydroxyvitamin D (25(OH)D) deficiency in children with biliary atresia (BA) and its effect on liver fibrosis. The serum vitamin D and 25(OH)D, and expression of 25 hydroxylase (CYP2R1 and CYP27A1) in the liver of BA patients were detected and compared with those in the control group. We investigated the effect of differential expression of CYP2R1 in hepatocytes on the expression of genes related to liver fibrosis in primary hepatic stellate cells (HSCs) of BA and animal models of cholestasis. The ratio of 25(OH)D/vitamin D in the BA group was significantly lower than that in the control group. The mRNA and protein expression of CYP2R1 and CYP27A1 in liver tissue of the BA group was significantly lower than that in the control group. Exogenous active vitamin D (calcitriol) inhibited the proliferation and migration of primary HSCs isolated from BA patients, and reduced the expression of fibrosis-related genes in vitro. Downregulation of expression of CYP2R1 in hepatocytes increased expression of transforming growth factor (TGF)-β1, collagen (Col)-1α1 and tissue inhibitor of metalloproteinase (TIMP)-1, and decreased the expression of matrix metalloproteinase (MMP)-2 in cocultured primary HSCs of BA. Upregulation of expression of CYP2R1 in mice with bile duct ligation significantly increased the level of 25(OH)D, decreased the expression of TGF-β1, Col-1α1 and TIMP-1, and increased the expression of MMP-2. Children with BA have impaired vitamin D activation due to CYP2R1 deficiency. The dysactivation of vitamin D can promote the proliferation and activation of HSCs and participate in the development of hepatic fibrosis in BA.
Highlights
Biliary atresia (BA) is the most common biliary obstructive disease and the most common cause of jaundice in infants[1,2]
Serum vitamin D was detected by ELISA; serum 25 hydroxyvitamin D (25(OH)D) level was detected by electrochemiluminescence; mRNA expression of CYP2R1,CYP27A1 and vitamin D receptor (VDR) in liver tissue was detected by quantitative real-time polymerase chain reaction; and protein expression of
The liver fibrosis of biliary atresia (BA) is earlier and more severe than any other infant cholestatic disease[3,4,5,6,7]; the presence of cirrhosis is often used for differential diagnosis of BA
Summary
Biliary atresia (BA) is the most common biliary obstructive disease and the most common cause of jaundice in infants[1,2]. The majority of these children still had progressive liver fibrosis, which eventually progresses to cirrhosis, gastrointestinal bleeding and liver failure within a few y ears[3]. Exploration of the molecular biological mechanism and influencing factors of progressive liver fibrosis in BA is the basis for further improvement of its clinical prognosis. Vitamin D deficiency is widespread and severe in children with BA, and the association between vitamin D and liver fibrosis in chronic liver disease has been confirmed in recent years. The present study aimed to explore the intrinsic molecular biological mechanisms of vitamin D activation disorder and liver fibrosis in children with BA, so as to provide a new theoretical basis and therapeutic target for the antifibrosis treatment of BA
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