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FOLIC ACID DEFICIENCY EXACERBATES BILIARY INFLAMMATION IN PRIMARY BILIARY CHOLANGITIS BY PROMOTING CHOLANGIOCYTE SENESCENCE
Date
May 18, 2024
Background and Objective: Biliary senescence in primary biliary cholangitis (PBC) patients is positively correlated with disease severity, prognosis, and poor UDCA response. Previous studies have shown that folic acid deficiency promotes cellular senescence, but its regulatory effects on cholangiocyte senescence remain unknown. This study aims to investigate whether folic acid deficiency exacerbates PBC biliary inflammation by promoting cholangiocyte senescence.
Methods: We measured the levels of folic acid in the serum of 44 PBC patients and 35 healthy controls, and compared the differences between the two groups. Additionally, we fed 4-month-old dnTGFβRII mice either a normal diet or a folic acid-deficient diet for 2 months. The severity of liver inflammation was assessed by evaluating liver pathology and inflammatory markers. Furthermore, the expression of P16 and P21 in liver tissue was assessed by qPCR and immunofluorescence to evaluate cholangiocyte senescence. In vitro experiments were conducted using human immortalized biliary epithelial cells (HIBEpiCs) pretreated with glycochenodeoxycholate (GCDCA) in a folate-deficient medium to investigate the effect of folate deficiency on cholangiocyte senescence.
Results: Compared to the healthy control group, PBC patients had reduced folic acid levels in the serum. Compared to the normal diet group, mice of the folic acid-deficient diet group showed increased expression of interleukin-1beta (IL-1β) in the liver, more infiltration of inflammatory cells in the periportal area observed in HE staining, increased expression of P21, and immunofluorescence staining showed that P21 expression was more prominent in cholangiocytes than hepatocytes. In vitro experiments demonstrated that folic acid deficiency significantly upregulated P21 expression in GCDCA treated cholangiocytes.
Conclusion: PBC patients have reduced folic acid levels, and folic acid deficiency exacerbates biliary inflammation in a mouse model of PBC by promoting cholangiocyte senescence, indicating folic acid deficiency plays an important role in the course of PBC.
Keywords: Primary biliary cholangitis; Folic acid; Cholangiocyte senescence
Methods: We measured the levels of folic acid in the serum of 44 PBC patients and 35 healthy controls, and compared the differences between the two groups. Additionally, we fed 4-month-old dnTGFβRII mice either a normal diet or a folic acid-deficient diet for 2 months. The severity of liver inflammation was assessed by evaluating liver pathology and inflammatory markers. Furthermore, the expression of P16 and P21 in liver tissue was assessed by qPCR and immunofluorescence to evaluate cholangiocyte senescence. In vitro experiments were conducted using human immortalized biliary epithelial cells (HIBEpiCs) pretreated with glycochenodeoxycholate (GCDCA) in a folate-deficient medium to investigate the effect of folate deficiency on cholangiocyte senescence.
Results: Compared to the healthy control group, PBC patients had reduced folic acid levels in the serum. Compared to the normal diet group, mice of the folic acid-deficient diet group showed increased expression of interleukin-1beta (IL-1β) in the liver, more infiltration of inflammatory cells in the periportal area observed in HE staining, increased expression of P21, and immunofluorescence staining showed that P21 expression was more prominent in cholangiocytes than hepatocytes. In vitro experiments demonstrated that folic acid deficiency significantly upregulated P21 expression in GCDCA treated cholangiocytes.
Conclusion: PBC patients have reduced folic acid levels, and folic acid deficiency exacerbates biliary inflammation in a mouse model of PBC by promoting cholangiocyte senescence, indicating folic acid deficiency plays an important role in the course of PBC.
Keywords: Primary biliary cholangitis; Folic acid; Cholangiocyte senescence
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