Diabetes researchers find switch for fatty liver disease

May 17, 2018, Duke University
Duke researchers have identified a key fork in the road for the way the liver deals with carbohydrates, fats and protein. A mutant version of the BDK protein was tagged with green fluorescent protein for an experiment to show it wouldn't enter the mitochondria (red). Credit: Duke Molecular Physiology Institute

Duke researchers have identified a key fork 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.

The finding is an outgrowth of the Duke Molecular Physiology Institute's "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, 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," 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 , 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?" 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," White said.

Through these experiments, the Duke team linked its findings to an enzyme that plays an important role in fat production in the liver. They showed that this enzyme, called ATP-citrate lyase, interacts with and is regulated by the same kinase and phosphatase that regulate BCAA metabolism. In a series of experiments, they established how and where these three factors interact in different parts of liver cells.

Working with Duke colleague Mark Herman, the researchers also found that a high-fructose diet (like drinking a lot of sugary soda), "creates an imbalance in the levels of the and phosphatase as part of a larger program that promotes fat accumulation in the liver," White said. Kinase activity goes up, phosphatase activity goes down—more bad guy, less good guy—leading to more fat and poorer metabolic health.

"This helps to explain how and why BCAA are associated with disordered fat metabolism that can lead to type 2 diabetes," said Newgard, who has worked on BCAA in for more than a decade.

"Chris' group has been a real leader in showing the importance of this," said Robert Gerszten MD, director of clinical and translational research for the Massachusetts General Hospital Heart Center. "There were hints about (BCAA) long ago, but the scientific world was sort of asking 'what's the cart and what's the horse?'" said Gerszten, who was not a part of this study.

"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," Gerszten said. "It gives us the motivation to test whether changes in the amino acid intake in our diets would be worth exploring."

These findings are limited by the use of only one kind of and the short duration of the study, but White is optimistic that longer-term studies in other animal models will bear them out. "Although much work remains to be done there's a potential for this to be a new target for treating ," White said.

Explore further: Blood test may predict future risk of cardiovascular events

More information: "The BCKDH Kinase and Phosphatases Integrate BCAA and Lipid Metabolism Via Regulation of ATP_Citrate Lyase," Phillip J. White, Robert W. McGarrah, Paul A. Grimsrud, Shih-Chia Tso, Wen-Hsuan Yang, Jonathan Haldeman, Thomas Grenier-Larouche, Jie An, Amanda L Lapworth, Inna Astapova, Sarah A. Hannou, Tabitha George, Michelle Arlotto, Lyra B. Olson, Michelle Lai, Guofang Zhang, Olga Ilkayeva, Mark A. Herman, R. Max Wynn, David T. Chuang, Christopher B. Newgard. Cell Metabolism, May 17, 2018. DOI: 10.1016/j.cmet.2018.04.015

Related Stories

Blood test may predict future risk of cardiovascular events

April 10, 2018
Despite heart disease and type 2 diabetes being among the leading causes of death in the U.S., the mechanisms leading to and linking these two diseases remain incompletely understood. A new study by investigators at Brigham ...

Diet low in specific amino acids may be the key to weight loss

December 21, 2017
A worldwide epidemic of diabetes and obesity has led many individuals to try to lose weight by dieting - but reduced-calorie diets are notoriously difficult to maintain. New research published in the Journal of Physiology ...

Set of molecules found to link insulin resistance in the brain to diabetes

October 9, 2014
A key mechanism behind diabetes may start in the brain, with early signs of the disease detectable through rising levels of molecules not previously linked to insulin signaling, according to a study led by researchers at ...

New link between gut bacteria and obesity

February 26, 2018
Researchers at Lund University in Sweden have discovered a new link between gut bacteria and obesity. They found that certain amino acids in the blood are connected to obesity and the composition of the gut microbiome.

Not all muscle building supplements are equal

July 14, 2017
Popular muscle building supplements, known as branched-chain amino acids (BCAA) are ineffective when taken in isolation, according to new research from the University of Stirling.

Recommended for you

Fat tissue may play a crucial role in the progression of diabetes, challenging long established notions

October 12, 2018
A new study by Australian researchers, out today, is challenging what we know about the causes of diabetes. The new research points to fat tissue as a source of disease, and widens our understanding beyond the traditional ...

Does breastfeeding hormone protect against type 2 diabetes?

October 12, 2018
(HealthDay)—The hormone prolactin—most commonly associated with breastfeeding—may play a role in reducing the risk of type 2 diabetes, a new study suggests.

Planned intermittent fasting may help reverse type 2 diabetes, suggest doctors

October 10, 2018
Planned intermittent fasting may help to reverse type 2 diabetes, suggest doctors writing in the journal BMJ Case Reports after three patients in their care, who did this, were able to cut out the need for insulin treatment ...

Markers of dairy fat consumption linked to lower risk of type two diabetes

October 10, 2018
Higher levels of biomarkers of dairy fat consumption are associated with a lower risk of developing type 2 diabetes, according to new research published today in PLOS Medicine. The study, in more than 60,000 adults, was undertaken ...

New discovery restores insulin cell function in type 2 diabetes

October 8, 2018
By blocking a protein, VDAC1, in the insulin-producing beta cells, it is possible to restore their normal function in case of type 2 diabetes. In preclinical experiments, the researchers behind a new study have also shown ...

Weight loss drug shows positive effect on diabetes

October 4, 2018
At the 2018 Meeting of the European Association for the Study of Diabetes, Brigham and Women's Hospital investigators from the Thrombolysis in Myocardial Infarction (TIMI) Study Group presented diabetes-related findings from ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.