Efforts to protect the body from the ill effects of alcohol have been the stuff of legends, dating back to the ancient Greeks and their erroneous beliefs around the power of the gemstone amethyst.

Today, UT Southwestern research into a hormone produced by the liver could have the potential to save thousands of lives lost each year to acute alcohol poisoning.

Steven Kliewer, Ph.D., Professor of Molecular Biology and Pharmacology, will detail his work related to this topic on Feb. 8 as the first speaker in this year’s President’s Lecture Series. The research, produced with longtime collaborator David Mangelsdorf, Ph.D., Chair and Professor of Pharmacology and an Investigator of the Howard Hughes Medical Institute, focuses on the hormone FGF21. In animal models mimicking binge drinking, the hormone dramatically accelerated the sobering process.

The 4 p.m. lecture, titled “Battle of the Bottle: Discovery of a Hormone Ally,” will take place in the Tom and Lula Gooch Auditorium.

Dr. Kliewer first came across FGF21 based on his long-running interest in nuclear receptors, which are proteins activated by hormones, vitamins, and other molecules. These proteins bind to DNA and regulate the expression of adjacent genes. After earning his Ph.D. at the University of California, Los Angeles, and finishing his postdoctoral fellowship at the Salk Institute in San Diego, he studied nuclear receptors while working at the pharmaceutical company Glaxo Inc., now known as GlaxoSmithKline. After Dr. Kliewer’s decadelong assignment there, Dr. Mangelsdorf – a former postdoctoral colleague at the Salk Institute – decided to join forces with his one-time scientific competitor and recruited him to UT Southwestern in 2002. Both Drs. Kliewer and Mangelsdorf are members of the National Academy of Sciences and of UT Southwestern’s Peter O’Donnell Jr. Brain Institute and Harold C. Simmons Comprehensive Cancer Center.

Early on, investigations in their combined lab at UTSW focused on the role of FGF21 in metabolism, since this hormone is turned on by a nuclear receptor called PPAR-α that’s the target of lipid-lowering drugs. But their work quickly shifted to FGF21’s role in alcohol consumption when research in the field revealed that ethanol – the type of alcohol in beer, wine, and spirits – prompted production of the hormone to increase manyfold.

Research from the Mangelsdorf/Kliewer Lab over the years has shown that FGF21 discouraged alcohol drinking in sober mice and encouraged water drinking to prevent dehydration in intoxicated mice. Other investigators have shown that the hormone appears to protect against alcohol-related liver injury.

In their most recent study, Dr. Kliewer, Dr. Mangelsdorf, and their colleagues showed that FGF21 can also dramatically speed the sobering process.

In animal modeling, injection with FGF21 cut in half the time required to regain consciousness in one comparison. In a second model more akin to typical human drinking behavior, FGF21 administration markedly accelerated recovery of coordination skills.

Dr. Kliewer explained that nothing is currently available to treat acute alcohol poisoning other than removing undigested alcohol from the stomach and providing supportive care, such as keeping patients warm and awake. Because FGF21 has already been explored in clinical trials involving diabetes, weight loss, and nonalcoholic fatty liver disease and has shown a good safety profile, it has potential to be developed into a drug that could be delivered to patients in hospital emergency rooms akin to the way Narcan is used to treat opioid overdoses.

Drs. Kliewer and Mangelsdorf recently launched a startup biotech company, Atias Pharma, and serve on the Scientific Advisory Board to pursue this goal. They are also collaborating with UTSW’s Whole Brain Microscopy Facility to study where FGF21 acts in the brain to drive the sobering process and investigating how alcohol turns on FGF21 in the liver.

Surprisingly little is known about how alcohol exerts its effects in the body. Dr. Kliewer said that is a gap that he, Dr. Mangelsdorf, and their colleagues hope to fill.

“This is definitely the most interesting and challenging research I have performed in my career and potentially the most impactful,” Dr. Kliewer said.