An international team of scientists have discovered that bile acid can turn off a receptor in the gut to prevent and reverse fatty liver disease in mice, and may help treat metabolic disorders such as obesity and type 2 diabetes. The study, titled “Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction,” was published in the journal Nature Communications.
Researchers fed a group of obese and diabetic mice glycine-beta muricholic acid (Gly-MCA) pills and a high-fat diet high diet, and found that these mice had significantly less fat and less resistance to insulin compared to an untreated group of mice.
The results revealed that Gly-MCA was able to selectively inhibit the farnesoid X receptor (FXR), a transcription factor responsible for regulating the expression of certain genes in tissues like those of the liver and intestine. Data also suggested that Gly-MCA may be a candidate for the treatment of metabolic disorders.
“Depending on the balance of conjugated and unconjugated bile acids, bacteria can modify these bile acid pools and turn off or turn on this receptor — FXR — in the gut,” said Frank Gonzalez, PhD, chief of the laboratory of metabolism at the National Cancer Institute, in a recent news release.
FXR is known to play a role in metabolic maintenance by detecting and controlling fats, glucose, and bile acids. Dr. Gonzalez said that the receptor’s role in the production and metabolism of fat might help to explain part of the compound’s anti-obesity effect.
The mice demonstrated metabolic benefits on only a small amount of the composite, an amount that in humans would be the equivalent of a daily single dose pill, said Andrew Patterson, associate professor of molecular toxicology, Penn State University. Dr. Patterson added the treatment was seen to be effective in both diet- and genetic-based forms of obesity and fatty liver disease.
FXR has been previously identified as a potential target to treat obesity and fatty liver disease. However, according to Dr. Gonzalez, the researchers faced numerous challenges in finding a composite that could operate in the complex intestinal system.
A team of scientists at Penn State Hershey College of Medicine, who assisted in the compound’s development, are hopeful that it can be developed in sufficiently large quantities at a reasonable price. “The preparation of a large quantity of the drug constituted a big challenge since very limited information was available in the literature and the drug was not commercially available,” said Dhimant Desai, associate professor of pharmacology, Penn State University College of Medicine.
Since bacteria, such as Lactobacillus, are known to break down the bile acids that further inhibit FXR, the investigators screened bile acids to determine which ones were resistant to bacteria. Gly-MCA was found to be resistant to the enzymatic activity of Lactobacillus bacteria lines. “Ideally what we would like to do is start looking at whether we can improve upon the current molecule to make more effective derivatives of Gly-MCA that are more resistant to bacterial hydrolyses and more potent at selectively inhibiting FXR,” Dr. Patterson said.
“The direction of this study is innovative and may open new avenues towards treating fatty liver, a very prevalent metabolic disorder in humans,” added Dr. Desai.
According to Dr. Patterson, more research is needed to better understand the mechanism, and to further evaluate the composite before its use human clinical trials.
In Western medicine, the use of bile acids is rare. However, Dr. Patterson said that bile acids have been used in a variety of treatments in Asian medicine and in ancient medical practices.
