The Effects of XBP1 Agonist IXA4 on Hepatic and Serum Bile Acid Levels of FXRKO vs. C57BL/6 Mice
Session Number
Project ID: MEDH 16
Advisor(s)
Dr. Richard Green, Northwestern University
Discipline
Medical and Health Sciences
Start Date
17-4-2024 10:00 AM
End Date
17-4-2024 10:15 AM
Abstract
Bile is essential to digestion because it solubilizes fats for absorption in the intestine. The rate-limiting step in bile acid synthesis is the addition of hydroxyl at the C-7 position of cholesterol by the hepatic enzyme Cholesterol 7-alpha hydroxylase (CYP7A1). The gene CYP7A1 is regulated by the Farnesoid X Receptor (FXR), which activates the Small Heterodimer Partner (SHP) suppressing CYP7A1. Cholestasis occurs when bile secretion is impaired and can injure the liver. This activates the Unfolded Protein Response, including the protein XBP1, which protects the liver from excess bile salts. IXA4 is an XBP1 agonist drug, and we tested the effects of IXA4 on FXR knockout mice. Methods: We treated FXRKO and C57BL/6 mice with 100mg/kg IXA4 for 48 hours. We used quantitative qPCR to measure gene expression of XBP1 downstream targets and using a spectrophotometric assay to measure serum and hepatic bile acid levels. Results: There was a 95% decrease in serum bile acid level (P < 0.05) and a 20% decrease trend in hepatic bile acids (P = 0.1116) in the treated FXRKO mice as opposed to those injected with vehicle solution. Conclusion: The IXA4 injection decreases serum and possibly hepatic bile acid levels, but further examination is required to determine the specific gene expression changes.
The Effects of XBP1 Agonist IXA4 on Hepatic and Serum Bile Acid Levels of FXRKO vs. C57BL/6 Mice
Bile is essential to digestion because it solubilizes fats for absorption in the intestine. The rate-limiting step in bile acid synthesis is the addition of hydroxyl at the C-7 position of cholesterol by the hepatic enzyme Cholesterol 7-alpha hydroxylase (CYP7A1). The gene CYP7A1 is regulated by the Farnesoid X Receptor (FXR), which activates the Small Heterodimer Partner (SHP) suppressing CYP7A1. Cholestasis occurs when bile secretion is impaired and can injure the liver. This activates the Unfolded Protein Response, including the protein XBP1, which protects the liver from excess bile salts. IXA4 is an XBP1 agonist drug, and we tested the effects of IXA4 on FXR knockout mice. Methods: We treated FXRKO and C57BL/6 mice with 100mg/kg IXA4 for 48 hours. We used quantitative qPCR to measure gene expression of XBP1 downstream targets and using a spectrophotometric assay to measure serum and hepatic bile acid levels. Results: There was a 95% decrease in serum bile acid level (P < 0.05) and a 20% decrease trend in hepatic bile acids (P = 0.1116) in the treated FXRKO mice as opposed to those injected with vehicle solution. Conclusion: The IXA4 injection decreases serum and possibly hepatic bile acid levels, but further examination is required to determine the specific gene expression changes.