Scientists look to a pathway in the gut to fix fatty liver disease

The buildup of fat in liver cells--which leads to nonalcoholic fatty liver disease (NAFLD)--has become a major public health issue. Now an international team of investigators that includes scientists at Penn State says they have their eyes on a potential pathway for new drug development.

Working with mice, which the investigators are quick to note are an imperfect model for this disease, the team disrupted intestinal farnesoid X receptor, or FXR, by targeting an intestinal bacteria with antibiotics, boosting levels of a bile acid called tauro-beta-muricholic acid. The bile acid in turn disrupted FXR, "a transcription factor that controls bile acid synthesis and transport in the liver and intestine."

"What our team found is that, if we genetically disrupt FXR expression in the intestinal epithelium, or inhibit it with tempol or antibiotics, we can prevent the development of NAFLD and obesity," said Andrew Patterson, an assistant professor of molecular toxicology at Penn State. "Now, this is in mice, so the next thing is to continue to take the next steps and, eventually, to see if FXR might be a suitable target in humans."

This isn't the first time this pathway has come up in the lab. And Intercept's closely watched OCA is a FXR agonist in development for nonalcoholic steatohepatitis, or NASH, which bears all the signs of liver disease seen in alcoholics, but in people who don't drink. The recent work, though, is likely to spur more lab experiments in potentially better therapies for preventing fatty liver disease.

In addition, this new study--published in the current issue of the Journal of Clinical Investigation--highlights the increased focus on the microbiome, the vast population of microorganisms that exist in every human being. But the investigators are also careful to point out that the digestive system in mice is not the same as the human system, which means that much more work has to be done to demonstrate that they are on the right path.

Adds Patterson: "What is exciting about this study, in particular, is that we feel like we are taking another small step in shedding some light on how diet and drugs can modulate bacteria and how these organisms modify their environment."

- here's the release
- read the research article

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