Application of lithocholic acid (LCA) in preparation of drug for relieving liver fibrosis

A technology of liver fibrosis and lithocholic acid, which is applied in the application field of medicine, can solve the problems of disappearance of biological energy and damage of cell membrane, and achieve the effect of reducing secretion, increasing intestinal relative abundance and reducing relative abundance.

Inactive Publication Date: 2021-01-15
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Ultimately leads to loss of bioenergy driven by proton pumps, causing immediate damage to cell membranes

Method used

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  • Application of lithocholic acid (LCA) in preparation of drug for relieving liver fibrosis
  • Application of lithocholic acid (LCA) in preparation of drug for relieving liver fibrosis
  • Application of lithocholic acid (LCA) in preparation of drug for relieving liver fibrosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1 LCA can inhibit liver inflammation and alleviate liver fibrosis

[0019] experimental method

[0020] 40 mice were randomly divided into 4 groups, 10 in each group.

[0021] Group 1: intraperitoneal injection of normal saline twice a week, gavage of deionized water twice;

[0022] Group 2: carbon tetrachloride model group (CCl4): olive oil 1:4, 1ul / g dose was injected intraperitoneally twice a week to mice. Oral administration of deionized water twice a week;

[0023] Group 3: Antibiotic treatment model intervention group (CCl4+LCA+VA): olive oil 1:4, 1ul / g dose was intraperitoneally injected to mice twice a week, and LCA was given to mice at a dose of 1mg / 15g by intragastric administration every week 2 times. Kill mouse intestinal flora with antibiotics (vancomycin 0.5g / L+ampicillin 1g / L is VA);

[0024] Group 4: Model intervention group (CCl4+LCA): olive oil 1:4, 1ul / g dose per intraperitoneal injection twice a week to mice, LCA 1mg / 15g dose intragastri...

Embodiment 2

[0028] Example 2 Interaction between LCA and intestinal flora

[0029] experimental method:

[0030] For each of the above groups, the fresh feces of the mice in each group were collected 24 hours before treatment, and frozen at -80°C. The intestinal flora among the mice in each group was detected by 16sRNA technology, and the differences in the flora among the groups were compared.

[0031] Experimental results:

[0032] It was found that the relative abundance of harmful bacteria Dubosiella (Dubosiella) decreased in the intestinal tract of LCA-administered mice, and the relative abundance of probiotics Lactobacillus and Bacteroides increased ( Figure 5 ). Antibiotics were used to kill intestinal symbiotic bacteria, and the effects of LCA on inhibiting liver inflammation and alleviating fibrosis disappeared. Demonstrate that the interaction of the gut microbiota-bile acid-liver triangle is the cornerstone of LCA action.

Embodiment 3

[0033] Example 3 LCA achieves anti-fibrosis effect by inhibiting liver NKT cell activator to reduce TNF-a concentration

[0034] experimental method:

[0035] The fresh liver of the mouse was taken, and the single cell suspension of the liver was prepared, and the immune cells in the liver: NKT cells, NK cells and macrophages, and the macrophages in the blood of the mice were detected by flow cytometry. The serum of the mice was detected by flow cytometric CBA.

[0036] Experimental results:

[0037]It was found that LCA can inhibit the activation of NKT cells, and the activation of NKT cells is manifested as down-regulation of NKT cells in liver tissue, which is related to the loss of specific antigens after NKT cell activation. After antibiotics kill the gut flora, the percentage of NKT cells increases. The change of TNF-α concentration in each group in serum is consistent with above-mentioned result ( Figure 5 ).

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Abstract

The invention relates to application of lithocholic acid (LCA) in bile acid in maintaining liver immune homeostasis, inhibiting inflammation and relieving liver fibrosis through interaction with intestinal flora, namely application of the LCA in preparation of a drug for relieving liver fibrosis. Specifically, in a mouse drug-induced hepatitis model made of CCl4, the LCA has the effects of reducing the number of NKT cells in the liver, reducing the concentration of TNF-a, inhibiting liver inflammation and finally relieving the progress of the liver fibrosis. After symbiotic bacteria in the intestinal tracts of mice are killed by antibiotics, the anti-inflammatory reaction of the LCA is weakened. The effect of the LCA in liver inflammation is mediated by intestinal microorganisms. The bileacid-micro-ecological-liver disease triangle may contribute to research and treatment of inflammatory liver diseases.

Description

technical field [0001] The invention relates to the use of lithocholic acid (LCA) in bile acids to maintain liver immune homeostasis, inhibit inflammation, and alleviate liver fibrosis by interacting with intestinal flora, that is, lithocholic acid is used in the preparation of medicines for alleviating liver fibrosis Applications. Background technique [0002] Bile acids are synthesized in the liver via cytochrome P450-mediated oxidation of cholesterol, including classical and alternative pathways. In the liver, bile acids are mainly coupled through glycine and taurine, and then transported to the gallbladder for storage through the bile salt export pump (BSEP). At the same time, the liver can also generate sulfonated and glucuronidated bile acids through the action of sulfotransferase and UDP-glucuronyltransferase, and then couple with glycine and taurine, through multidrug resistance-associated protein 2 ( MRP2) is transported and secreted into the gallbladder. In the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/575A61P1/16A61P29/00
CPCA61K31/575A61P1/16A61P29/00
Inventor 陈智邵骏威朱海红连雯雯
Owner ZHEJIANG UNIV
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