May 18, 2018 - 16:24 AMT
PanARMENIAN.Net - Duke researchers have identified a key in the road for the way the liver deals with carbohydrates, fats and protein. They say it could be a promising new target for combating the pandemics of fatty liver disease and prediabetes, Drug Target Review reports.
The finding is an outgrowth “retro-translation” approach, in which bloodstream markers of a particular disease are identified by broad screens and then “taken back into animal models to figure out what that signal means,” said Phillip White, an Assistant Professor of medicine who led the study.
In this case, Prof White and colleagues were pursuing a cluster of amino acids — breakdown products of protein metabolism — that seemed to signal insulin resistance. They’re called branched-chain amino acids, or BCAA, and had been identified in 2009 as a robust marker of obesity and insulin resistance in humans by Duke researchers led by Christopher Newgard, the director of the Duke Molecular Physiology Institute.
The association between BCAA and insulin resistance had been present in the literature dating back to a 1969 study that appeared in the New England Journal of Medicine. And they have since been shown to be highly predictive of future diabetes development by the landmark Framingham Heart Study.
“These metabolites travel together with poor metabolic health,” Prof White said. “There’s a longstanding historical record of this, but we don’t know what it means.”
In probing the biochemistry of how BCAAs come to be more abundant in obesity and insulin-resistance, researchers have found that different organ systems handle their breakdown in different ways. In the liver, which stores more fat and produces more glucose in prediabetes, it turns out that the molecular components that execute BCAA breakdown are turned off by a single regulatory switch.
Two molecules, a kinase and a phosphatase, work in opposition to flip this regulatory switch that controls the break down of BCAA. The balance of these molecules determines whether BCAAs are broken down or accumulate.
“Well, what if we turn it back on?” Prof White asked. “We can take away the inhibitory signal, the kinase, or add more of the activating signal, the phosphatase.” This approach was aided by a collaboration with the group of Drs David Chuang and Max Wynn at the University of Texas Southwestern Medical Center, Dallas, who had discovered a drug that inhibits the kinase.
When the researchers inhibited the kinase or activated the phosphatase, the results were almost identical. Within a week in a rat model of prediabetes, activating BCAA breakdown reduced fat deposition in the liver and improved glucose regulation without altering body weight.
“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,” Prof White said.