Traditional Chinese medicine believes that bear bile can clear heat, promote gallbladder, calm liver, detoxify, and can be used to protect liver and eyesight. Dr. Yunjing Zhang from the Translational Medicine Center of Shanghai Sixth People's Hospital, China observed the dynamic effects of Ursodeoxycholic acid (UDCA) on the enterohepatic circulation of bile acids and studied the mechanism in depth, and published in the British Journal of Pharmacology. superior. Studies have found that UDCA can inhibit the intestinal FXR signaling pathway after combining with glycine or taurine, and increase the expression of bile acid transporter (sodium dependent bile acid transporter, ASBT) in the terminal ileum, promote bile acid At the same time, the expression of fibroblast growth factor 15/19 (fibroblast growth factor 15/19, FGF15/19), a signaling molecule downstream of the intestinal FXR signaling pathway, was reduced, and low levels of FGF15/19 enhanced hepatic bile acid transporters. (such as bile salt export pump, bile-saltexport pump, BSEP, etc.), and weaken the inhibition of cholecystokinin, thereby accelerating the enterohepatic circulation, promoting the excretion of bile acids through feces, and reducing the bile acid pool. This study proves that UDCA plays an important role in maintaining the homeostasis of bile acids, supplements people's understanding of the pharmacological mechanism of ursodeoxycholic acid, and provides new ideas for related research on bile acid metabolism.
Pharmacological effects of ursodeoxycholic acid （UDCA）
1. Replace toxic bile acids
Cholestasis in the liver reaches a certain toxic concentration, which can lead to necrosis, apoptosis, fibrosis and even cirrhosis. Taking UDCA (13-15mg/kg/day) continuously, the conjugated UDCA will become the main bile acid component in serum, liver and bile, which makes the originally hydrophobic and highly toxic endogenous bile acid replaced by strong hydrophilicity. UDCA alternative.
2. Cell protection
The cytoprotective effects of UDCA are manifested in membrane stability and anti-apoptosis. This may be because UDCA and bound UDCA can be combined in different regions of the cell membrane respectively, the bound UDCA is attached to the surface of the cell membrane, and the unbound UDCA is inserted into the non-polar domain of the cell membrane, so as to jointly stabilize and protect the cell membrane. , effective against the damaging effects of hydrophobic bile acids. In addition, UDCA has been found to have anti-apoptotic effects in a number of in vitro and in vivo experiments. UDCA and different pro-apoptotic substances were added to hepatocytes and non-hepatocytes for culture, and it was found to inhibit 50%-100% of apoptosis. It was also found that UDCA can reduce mitochondrial membrane permeability, which may be one of the important reasons for UDCA to resist apoptosis.
3. Immune regulation
The major histocompatibility complex (MHC) is expressed in the liver cell membrane and cytoplasm of patients with PBC or primary sclerosing cholangitis (PSC), and the use of UDCA can reduce its expression. In addition, UDCA can activate the glucocorticoid receptor (glucocorticoid receptor, GR). After clinical use of UDCA, it was found that UDCA can also inhibit IgM, IgG and IgA produced by B lymphocytes, and relieve the immune response by inhibiting the release of inflammatory factors from monocytes.
4. Promote bile secretion
UDCA can improve the function and expression of Cl-/HCO3- cotransporter AE2 (anionexchanger 2, AE2), which is a key transporter responsible for bile efflux from bile ducts. In addition, UDCA can also upregulate the expression of bile acid transporters measured in hepatocyte capillary bile ducts, such as BSEP and MRP2, thereby promoting the efflux of amino-binding, glucuronic, and sulfated bile acids.
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