Duke team IDs new target for fatty liver disease and prediabetes

The buildup of fat in the liver known as nonalcoholic fatty liver disease now affects up to 25% of Americans, according to the American Liver Foundation, leading many experts in metabolic disorders to dub it a pandemic. The rise of the disease tracks with increasing obesity rates, though nonobese people can develop it, too. People with prediabetes face a high risk of developing fatty liver disease, and there are no cures.

Scientists at Duke have identified a pathway in the liver that they believe could be manipulated to reduce the deposition of fat in the liver. It involves balancing two enzymes that work against each other to control fat metabolism. When they tried their method in rat models of obesity and metabolic disease, they found they could lower the amount of fat deposited in the liver and improve glucose regulation. They published their study in the journal Cell Metabolism.

The key to the discovery lies in branched-chain amino acid (BCAA), which is produced when protein is metabolized. Scientists have long known of an association between BCAA, obesity and insulin resistance, but they’ve struggled to figure out the mechanisms behind that link.

So researchers at the Duke Molecular Physiology Institute focused on two enzymes that control how BCAA is broken down in the body: one a kinase that inhibits the breakdown and the other a phosphatase that activates it.

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First they took a kinase-inhibiting drug developed at the University of Texas Southwestern Medical Center and tested it in the rat model. Then they found a way to activate phosphatase. Both experiments produced the same result: less fat in the liver and better glucose control. And the improvements started to show within a week.

"This particular rat model (the Zucker fatty rat) is an extreme model of obesity and metabolic disease, so if you can get an improvement in a week, that's really significant," said lead author Phillip White, Ph.D., an assistant professor of medicine, in a statement.

It’s the latest example of how new insight into enzyme activity is advancing research in diabetes and related disorders. In March, a team at Columbia University demonstrated in rodents that if they shut down the production of the enzyme DPP4 in the liver, they could improve insulin resistance. And a team in Japan published research in January suggesting that Sir2 could be targeted to improve glucose uptake in the liver.

The Duke team is planning further experiments to better understand how BCCA can be targeted in fatty liver disease and prediabetes. But their observations in the Zucker fatty rat are already motivating some specialists to consider new strategies for treating metabolic disorders.

"There's growing evidence to suggest that BCAA isn't just a passive marker of diabetes, but may actually play a role in driving the disease," said Robert Gerszten, M.D., director of clinical and translational research for the Massachusetts General Hospital Heart Center, in the statement. "It gives us the motivation to test whether changes in the amino acid intake in our diets would be worth exploring."