Bile Acid-FXR Pathways Crucial to Liver Physiology, Diseases

Too much bile acids can lead to damage in the cell membranes and can cause cell death and inflammation.

Bile acid-farnesoid X receptor (FXR)-fibroblast growth factor (FGF)15/19 is an important part of liver physiology and diseases, in addition to being drug targets; however, the long-term effects of these treatments are unknown, according to a session at the virtual 81st American Diabetes Association Scientific Sessions.

Grace L. Guo, MBBS, PhD, associate professor in the Pharmacology and Toxicology Department at Rutgers University, discussed how bile acid functions can help in many ways with diseases such as steatohepatitis.

“It is important because they are a natural mechanism to eliminate cholesterol and are also the main driving force for bile flow,” Guo said.

However, too much bile acids can lead to damage in the cell membranes and can cause cell death and inflammation. Guo mentioned how dysregulation is more strongly associated with human diseases, such as gallstones and inflammatory bowel disease, or an altered energy homeostasis, which is the reasoning behind her calling bile acids a “double-edged sword.”

When looking at humans versus other species, the bile acid receptor, also called the farnesoid X receptor (FXR) or NR1H4, is highly expressed in the liver, intestine, kidneys, and adrenals. In addition, the receptor is a major regulator of bile acid homeostasis. In terms of FGF15/19, it is the most potent carcinogen in the gut; however, differences in FGF15 by species is almost exclusively expressed in helium versus FGF19 in the gallbladder, according to Guo.

Although the FXR pathway is important to regulate overall bile acid levels, there is reduced FXR expression and activity in human patients with non-alcoholic steatohepatitis (NASH) versus what has been seen in mice.

Guo mentions how human FXR is not as abundant and a lower FXR expression in liver and colon diseases could be an important target for future human disease research.

“With modified FGF19 used in NASH, it can be effective in reducing steatohepatitis,” Guo said. “This can be very important to understand the pathways for future research and development.”

REFERENCE

Guo GL. Pharmacologic Utilization of Bile Acid-FXR Pathway to Treat Nonalcoholic Steatohepatitis. Session presented at: American Diabetes Association 81st Scientific Sessions Virtual; June 25-29, 2021. Accessed June 25, 2021.