Liver-produced hormone protects mice against the harmful effects of intoxication

A shot of a liver-produced hormone called FGF21 sobered up mice that had passed out from alcohol, allowing them to regain consciousness and coordination much faster than those that didn't receive this treatment, UT Southwestern researchers report in a new study. The findings, published in Cell Metabolism, could lead to effective treatments for acute alcohol intoxication, which is responsible for about 1 million emergency room visits in the U.S. each year.

Humans have long searched for agents that could reverse drunkenness, and now we have discovered something to achieve this effect that's been in our bodies the whole time."

David Mangelsdorf, Ph.D., Chair and Professor of Pharmacology, Professor of Biochemistry at UTSW, and a Howard Hughes Medical Institute Investigator

Dr. Mangelsdorf co-led the study with his longtime collaborator, Steven Kliewer, Ph.D., Professor of Molecular Biology and Pharmacology, and Mihwa Choi, Ph.D., an Instructor of Pharmacology.

Dr. Kliewer explained that for thousands of years, humans have attempted to speed up the sobering process after drinking too much alcohol. For example, the ancient Greeks believed that amethyst could protect people from drunkenness, so they drank out of chalices carved from this semiprecious stone. But there is no treatment for alcohol intoxication. Other than removing undigested alcohol by pumping the stomach and preventing people from aspirating their own vomit, getting sober takes time, Dr. Mangelsdorf said.

In recent years, Drs. Mangelsdorf, Kliewer, and their colleagues discovered that FGF21 discouraged alcohol drinking in sober mice and encouraged water drinking to prevent dehydration in intoxicated mice. Other researchers discovered that this hormone appears to protect against alcohol-related liver injury.

While further exploring the hormone, UTSW scientists discovered that mice genetically altered to delete the gene that produces FGF21 took far longer than unaltered mice to become sober after acute alcohol poisoning.

As part of this latest study, the researchers delivered enough alcohol to mice to render them unconscious, mimicking a binge drinking session. They then injected some of the animals with FGF21. While those that didn't receive this agent took about three hours to regain consciousness and stand upright, those that received FGF21 were able to accomplish this feat in half the time.

When the researchers delivered smaller amounts of alcohol more akin to typical human drinking – enough to significantly affect the animals' coordination – the mice that received FGF21 injections also regained their coordination much faster than those that didn't receive the hormone.

Further investigations showed that FGF21 acts on noradrenergic neurons, a type of nerve cell in the brain that promotes wakefulness. The hormone didn't affect alcohol metabolism, though, as both treated and untreated mice showed the same blood alcohol concentrations.

FGF21 appears to specifically affect intoxication from alcohol, Dr. Kliewer said. Animals that received other types of sedatives did not become alert any faster than usual when given this hormone.

Dr. Mangelsdorf added that FGF21 has already been explored in clinical trials involving diabetes, weight loss, and nonalcoholic fatty liver disease and has shown a good safety profile. Eventually, he said, FGF21 could be developed into a drug that could be delivered to patients in hospital emergency rooms, college campuses, or elsewhere akin to the way Narcan is used to treat opiate overdoses, potentially saving countless lives.

"We don't want to send the signal that it's OK to get drunk because a drug can undo it," Dr. Kliewer said. "But FGF21 may eventually be able to prevent some negative consequences for people incapacitated from alcohol."

Other UTSW researchers who contributed to this study are Wei Fan, Abhijit Bugde, Laurent Gautron, Kevin Vale, Robert E. Hammer, and Yuan Zhang.