Caffeic acid phenethyl ester suppresses intestinal FXR signaling and ameliorates nonalcoholic fatty liver disease by inhibiting bacterial bile salt hydrolase activity.

Abstract

Propolis is commonly used in traditional Chinese medicine. Studies have demonstrated the therapeutic effects of propolis extracts and its major bioactive compound caffeic acid phenethyl ester (CAPE) on obesity and diabetes. Herein, CAPE was found to have pharmacological activity against nonalcoholic fatty liver disease (NAFLD) in diet-induced obese mice. CAPE, previously reported as an inhibitor of bacterial bile salt hydrolase (BSH), inhibited BSH enzymatic activity in the gut microbiota when administered to mice. Upon BSH inhibition by CAPE, levels of tauro-β-muricholic acid were increased in the intestine and selectively suppressed intestinal farnesoid X receptor (FXR) signaling. This resulted in lowering of the ceramides in the intestine that resulted from increased diet-induced obesity. Elevated intestinal ceramides are transported to the liver where they promoted fat production. Lowering FXR signaling was also accompanied by increased GLP-1 secretion. In support of this pathway, the therapeutic effects of CAPE on NAFLD were absent in intestinal FXR-deficient mice, and supplementation of mice with C16-ceramide significantly exacerbated hepatic steatosis. Treatment of mice with an antibiotic cocktail to deplete BSH-producing bacteria also abrogated the therapeutic activity of CAPE against NAFLD. These findings demonstrate that CAPE ameliorates obesity-related steatosis at least partly through the gut microbiota-bile acid-FXR pathway via inhibiting bacterial BSH activity and suggests that propolis enriched with CAPE might serve as a promising therapeutic agent for the treatment of NAFLD.

• Authors: Xian-Chun Zhong, Ya-Meng Liu, Xiao-Xia Gao, Kristopher W Krausz, Bing Niu, Frank J Gonzalez, Cen Xie
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 44 Issue 1 Pg. 145-156 (Jan 2023) ISSN: 1745-7254 [Electronic] United States
• PMID: 35655096 (Publication Type: Journal Article)
• Copyright: © 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Chemical References

• choloylglycine hydrolase
• caffeic acid phenethyl ester
• Propolis
• Ceramides
• Bile Acids and Salts

Topics

• Mice
• Animals
• Non-alcoholic Fatty Liver Disease (drug therapy, metabolism)
• Propolis (metabolism, pharmacology, therapeutic use)
• Intestines
• Liver (metabolism)
• Obesity (drug therapy)
• Bacteria (metabolism)
• Ceramides (metabolism)
• Bile Acids and Salts (metabolism)
• Mice, Inbred C57BL