A study published in Nature Communications showed that blocking the farnesoid X receptor (FXR) specifically in the intestine with an oral inhibitor improved the metabolic profile of obese mice, even in short-term experiments where it did not lead to weight loss.

The work appeared in the Dec. 15, 2015, online issue.

"We were able to identify the gut as a really important place to target the farnesoid X receptor" for effects on the liver, corresponding author Andrew Patterson, an associate professor of molecular toxicology at Pennsylvania State University, told BioWorld Today.

Bile acids are the major component (other than water) of bile, which aids in the digestion of lipids. Bile figured prominently in the humors-based approach that was developed by Hippocrates and dominated Western medicine until the 19th century.

The humors concept ultimately proved less beneficial than the Hippocratic oath. But bile is important for digestion, and it affects metabolic processes.

FXR is a nuclear receptor that both senses and regulates the level of bile acids. Its role in regulating metabolism is complex, and there is some controversy about whether FXR activity needs to be increased or decreased for metabolic benefits.

There are drug discovery efforts with both FXR agonists and antagonists, though at this point, the agonists are further along in the clinic. Intercept Pharmaceuticals Inc. has filed for FDA approval for its FXR agonist, obeticholic acid, in primary biliary cirrhosis. Obeticholic acid is also in phase III trials for nonalcoholic steatohepatitis, or fatty liver, and in phase II for other metabolic disorders. Novartis AG's LJN-452 is in phase II for both indications.

Some data also suggest that changes in FXR activity are an important consequence of bariatric surgery, though clear data are hard to come by.

There are also studies, however, that suggest that inhibiting FXR can be beneficial under certain circumstances, and in certain anatomical locations. The work now published in Nature Communications adds to that evidence.

"We are suggesting that turning it off is beneficial," Patterson said.

Many bile acids are metabolized by gut bacteria, adding another layer of complexity. In animals without a gut microbiome, certain types of bile acids go up and, as a result, FXR goes down.

In their paper, the researchers described identifying glycine-beta-muricholic acid (Gly-MCA) as a bile acid that inhibited the FXR, and was not metabolized by gut bacteria.

In their work, Patterson and his colleagues looked at Gly-MCA-s effects on both obesity itself and on insulin resistance and hepatic steatosis or fatty liver, which are metabolic consequences of obesity. Chronic treatment with Gly-MCA prevented weight gain in mice that were fed a high-fat diet, improved their insulin sensitivity and protected them from fatty liver disease.

Treated mice did not eat significantly less than control animals. Instead, they expended more energy. The authors showed that this was caused by the activation of so-called beige fat – fat cells that should be energy-storing white cells in terms of their lineage but instead are running energy-burning brown fat gene expression programs. Gly-MCA inhibited the production of ceramides in the gut, and lower ceramide levels affected subcutaneous fat cells.

While much of the research into FXR has focused on the gut and the liver, FXR is expressed in many places. Whole-body knockouts have multiple metabolic problems and are also more prone to cancer.

Given that state of affairs, one of Gly-MCA's benefits is actually its poor bioavailability, which prevented it from reaching the liver when it was given orally. The authors also showed that mice lacking FXR only in the gut did not benefit from Gly-MCA treatment, confirming that though the effects were ultimately seen in the liver, the compound was acting in the gut.

Patterson, co-corresponding author Frank Gonzalez, of the National Cancer Institute, and their colleagues plan to develop follow-on compounds with higher potency, as well as carry out longer-term toxicity studies.

Patterson said that ultimately, the team hopes that it could be possible to treat fatty liver by inhibiting FXR in the gut. "If we can selectively modulate the activity of the receptor in one tissue compartment," he said, "perhaps we can [achieve] beneficial effects in another compartment."