Navigation Links
PHACCS, an online tool for estimating the structure and diversity of uncultured viral communities using metagenomic information

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. Nonlinear Dynamics announces more details of its global partnership with PerkinElmer
2. New online portal merges vast data on Gulf of Maine ecosystem
3. DOE JGI launches IMG public online microbial genome data clearinghouse
4. Microbiology text tells stories, offers online resources
5. Brain maps online
6. Man and mouse share genome structures
7. Scientists solve structure of key protein in innate immune response
8. Vascular structure and function improve with diet and exercise
9. Biochemists report discovery of structure of major piece of telomerase; implications for cancer
10. SuperLigands - a database of ligand structures derived from the Protein Data Bank
11. DNA constraints control structure of attached macromolecules
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:3/30/2017)... 30, 2017 The research team of The ... (3D) fingerprint identification by adopting ground breaking 3D fingerprint minutiae recovery ... of speed and accuracy for use in identification, crime investigation, immigration ... ... A research team ...
(Date:3/28/2017)... -- The report "Video Surveillance Market by ... Devices), Software (Video Analytics, VMS), and Service (VSaaS, Installation ... 2022", published by MarketsandMarkets, the market was valued at ... reach USD 75.64 Billion by 2022, at a CAGR ... considered for the study is 2016 and the forecast ...
(Date:3/24/2017)... Research and Markets has announced the addition ... Trends - Industry Forecast to 2025" report to their offering. ... The Global Biometric ... of around 15.1% over the next decade to reach approximately $1,580 ... market estimates and forecasts for all the given segments on global ...
Breaking Biology News(10 mins):
(Date:9/22/2017)... Springfield, Mo. (PRWEB) , ... September 22, 2017 ... ... company, recently announced it will host a booth at premier packaging event PACK ... is hosted by the Packaging Machinery Manufacturers Institute (PMMI). , At this year’s ...
(Date:9/22/2017)... ... September 22, 2017 , ... The effectiveness of a ... in clinical trials in the United States. (clinicaltrials.gov : NCT02973893) , To find ... or find your nearest participating clinic here https://factor-therapeutics.com/clinical-trials/ and discuss your ...
(Date:9/21/2017)... ... (PRWEB) September 21, 2017 , ... The 3rd ... to review the latest knowledge on these products, which are increasingly used in ... the impact of Biostimulants on Plant Nutrition, Abiotic Stresses, Plant Growth and Development, ...
(Date:9/21/2017)... ... 21, 2017 , ... Today, BioPharma Institute, a leading training ... of 5 new courses to its prospectus. These include the eagerly-awaited Regulation ... 11 on Electronic Records and Electronic Signatures (Part 11 of Title 21 of ...
Breaking Biology Technology: