Navigation Links
Eliminate Data Analysis Bottlenecks in Drug Discovery

In the March 3 issue of Nature, Johns Hopkins researchers report that two proteins best known for very different activities actually come together to turn the liver into a sugar-producing factory when food is scarce. Because the liver's production of sugar is a damaging problem in people with diabetes, the proteins' interaction might be a target for future drugs to fight the disease, the researchers say.

Under normal circumstances, the liver's production of sugar is a back-up plan that enables survival during food shortages; the brain and certain other critical organs rely on sugar -- specifically glucose -- for the energy to function. In people with diabetes, however, the liver doesn't sense the incoming calories, and it keeps making glucose when it shouldn't.

The researchers discovered that, in fasting mice, the liver's production of sugar kicked into high gear because amounts and activities of the two proteins, called sirtuin1 and PGC1-alpha, increased when dietary calories weren't available. Once mice were fed, levels of the two proteins went down and sugar production ceased.

"It isn't a coincidence," says Pere Puigserver, Ph.D., an assistant professor of cell biology at the Johns Hopkins University School of Medicine's Institute for Basic Biomedical Sciences. "The two proteins actually bind to each other, and without sirtuin1, PGC1 can't make glucose."

A current diabetes-fighting drug, metformin, blocks steps in the glucose-making process, but the new research identifies a critical regulatory step the researchers say could be targeted as well.

PGC1, which Puigserver isolated and cloned in 1998 as a postdoctoral fellow at Harvard, controls gene expression in the liver and other tissues. In the liver, it triggers the conversion of fats into sugar, particularly when access to food is limited. But no one knew exactly how it was controlled or what else it might need in order to launch the sugar-making process.

Sirtuin1, like its sirtuin relatives, is best known for removing molecular "decorations" on proteins that help organize DNA and restrict access to genes. It turns out that sirtuin1 also removes these decorations from PGC1, and then remains bound to PGC1 as it starts up the sugar-making process, the researchers found.

"Because both proteins are required for the liver to make sugar, targeting sirtuin1 in a very specific way might help control sugar production in people with diabetes," says Puigserver. "Sirtuin1 interacts with many different proteins, and it's just this one interaction you would want to prevent."

But, he says, PGC1 has an unusually close relationship with sirtuin1 that may make for relatively easy picking. PGC1, unlike the vast majority of proteins, only uses sirtuin1 to remove its "decorations," called acetyl groups. Most other proteins can have the groups plucked off by a number of different enzymes.

"PGC1 is a 'clean' target for sirtuin1," says Puigserver. "If sirtuin1 isn't available, PGC1 becomes covered in acetyl groups, and the acetyl-covered PGC1 can't make sugar."

In their experiments, graduate student Joseph Rodgers also discovered that the livers of fasted mice first developed high levels of a chemical called pyruvate, which is a starting material for making glucose, and then accumulated high levels of sirtuin1 protein. (Rodgers will receive the Nupur Dinesh Thekdi Research Award on April 14 for this work as part of the School of Medicine's 28th annual Young Investigators' Day celebration.)

"When there's no incoming food, muscles make lactate and alanine and send them to the liver to be converted into pyruvate and glucose," says Puigserver. "It appears, from our work, as though the pyruvate then triggers increased production of sirtuin1, which in turn lets PGC1 start converting the pyruvate into the glucose the body needs to survive."

The relationship between sirtuin1 and PGC1 also connects processes in volved in cellular aging and responding to calorie intake in mammals for the first time. In bacteria and yeast, the equivalent of sirtuin1 is already known to help slow processes linked to cellular aging when food is scarce, an effect that extends the single-celled organism's lifespan.

"We now know that sirtuin1 is directly involved in the response to calorie restriction in mammals and in processes involved in cellular aging," says Puigserver. "But we still don't know whether sirtuin1's activity affects lifespan in mammals."

There is a precarious anecdotal link, however. In 2003, other scientists reported that a compound found in red wine activated yeast's sirtuin1-equivalent and extended the organism's lifespan. Moving up the food chain, decades of reports have shown that drinking moderate amounts of red wine is associated with a longer life for people.

But at this point, knowing for sure whether sirtuin1 helps extend lifespan (an organism issue) or is merely involved in cellular aging (a cell-by-cell issue) in mammals will take much more work. Sirtuin1's potential as a target for treating diabetes is much closer, says Puigserver.

The researchers are now probing the pyruvate-sirtuin1 connection more closely and looking for more details of the sirtuin1-PGC1 interaction. Also on the to-do list: examining sirtuin1 and PGC1 in other tissues, particularly muscle and fat, two other energy-producing tissues in mammals.

The study was funded by the Ellison Medical Foundation, the American Federation for Aging Research, and start-up funds from the Department of Cell Biology at the Johns Hopkins School of Medicine.

Authors on the paper are Rodgers, Puigserver and Carlos Levin of Johns Hopkins; and Wilhelm Haas, Steven Gygi and Bruce Spiegelman of Harvard Medical School.


'"/>

Source:


Related biology news :

1. Ariadne Genomics Announces the Release of PathwayStudio?Central, Client-Server Software for Biological Pathway Analysis
2. Analysis Of Human Genome To Predict The Development Of Illnesses
3. Analysis of flower genes reveals the fate of an ancient gene duplication
4. Genomatix Microarray Analysis Pipeline achieves Affymetrix GeneChip compatible?status
5. Analysis of breast-cancer gene role offers promising target
6. Analysis of rhesus monkey genome uncovers genetic differences with humans, chimps
7. Fundamental Finding Yields Insight into Stem Cells, Cancer; Opens Door to Drug Discovery
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:11/14/2016)... 14, 2016  xG Technology, Inc. ("xG" or the ... wireless communications for use in challenging operating environments, announced ... 2016. Management will hold a conference call to discuss ... Eastern Time (details below). Key Recent Accomplishments ... million binding agreement to acquire Vislink Communication Systems. The ...
(Date:6/22/2016)... BETHESDA, Md. , June 22, 2016  The American ... by Trade Show Executive Magazine as one of ... Summit on May 25-27 at the Bellagio in ... based on the highest percentage of growth in each of ... number of exhibiting companies and number of attendees. The 2015 ...
(Date:6/21/2016)... VANCOUVER, British Columbia , June 21, 2016 ... been appointed to the new role of principal ... has been named the director of customer development. ... , NuData,s chief technical officer. The moves reflect ... development teams in response to high customer demand ...
Breaking Biology News(10 mins):
(Date:12/5/2016)... ... December 05, 2016 , ... In anticipation of AxioMed’s exclusive ... production, company President, Jake Lubinski will be traveling to Germany on December 6th. ... Cologne and Karlsruhe to discuss the benefits of a viscoelastic total disc replacement. ...
(Date:12/5/2016)... , Dec. 5, 2016  Eisai Inc. ... open-label two-year study of rufinamide, which were presented ... Epilepsy Society (AES) held from December 2-6 in ... final two-year safety, tolerability and cognitive data showed ... experienced similar safety and tolerability profiles, cognitive development ...
(Date:12/4/2016)... 2016  In five studies being presented today during ... and Exposition in San Diego , ... the delivery of life-saving treatments to patients with a ... to carry therapies directly to the sites in the ... a substantial advantage over traditional, systemic methods. The studies ...
(Date:12/2/2016)... Amgen (NASDAQ: AMGN ) and Allergan ... of a Marketing Authorization Application (MAA) to the European Medicines ... ® (bevacizumab). The companies believe this submission is the ... "The submission of ABP 215 to the EMA is ... portfolio," said Sean E. Harper , M.D., executive vice ...
Breaking Biology Technology: