The discovery by researchers in Hopkins' Institute of Basic Biomedical Sciences and McKusick-Nathans Institute for Genetic Medicine reveals that a protein called GCN5 is critical for controlling a domino-like cascade of molecular events that lead to the release of sugar from liver cells into the bloodstream. Understanding the role of GCN5 in maintaining blood sugar levels is leading to a clearer picture of how the body uses sugar and other nutrients to make, store and spend energy.
"Understanding the ways that energy production and use are controlled is crucial to developing new drugs and therapies," says the report's senior author, Pere Puigserver, Ph.D., an assistant professor of cell biology at Hopkins.
The inability to properly regulate blood sugar levels leads to conditions like obesity and diabetes. Both type 1 and type 2 diabetes cause blood sugar levels to stay too high, which can lead to complications like blindness, kidney failure and nerve damage.
"Diabetes is a really big problem, even when patients are given insulin and stay on strict diets," says Carles Lerin, Ph.D., a postdoctoral fellow in cell biology at Hopkins and an author of the report. "In the absence of a cure for the disease, we are really trying to focus on finding better treatment because currently available methods just don't work that efficiently," he says.
The body keeps blood sugar – known as glucose – within a narrow range. Extra glucose floating through the bloodstream, which is common after eating a meal, is captured and kept in the liver. When blood glucose runs low, the liver releases its stores back into the bloodstream. When those reserves are tapped out, liver cells turn on genes to make more glucose to fuel the body.
The research team found that GCN5 chemically alters another protein called PGC-1alpha that normally turns on a set of genes to manufacture enzymes required for glucose release. When GCN5 is fully functional in liver cells, this cascade is turned off and glucose is not released from those cells. Removal of functional GCN5 from liver cells restores the cells' ability to release glucose.
The researchers showed that GCN5 alters its target, sabotaging it by adding a chemical tag called an acetyl group. By using molecules that glow fluorescently, the researchers saw under high-power microscopes that GCN5 carries its tagged target to a different location in the cell's nucleus – sequestering it away from the genes it's normally meant to turn on.
"GCN5 has been generally shown to turn on genes. No one knew that GCN5 could be used to turn off pathways" says Lerin. "It was a bit of a surprise."
When the researchers put GCN5 into live mice, they found that it can in fact decrease blood glucose levels. Liver cells in mice that were given no food for 16 hours actively release glucose into the bloodstream. Introducing GCN5 into their livers, however, causes blood glucose levels in these mice to be reduced.
"These results show that changing GCN5 is sufficient to control the sugar balance in mice," says Puigserver. "Therefore, GCN5 has the potential to be a target for therapeutic drug design in the future."
The researchers were funded by the Secretaria de Estado de Universidades e Investigacion del Ministerio de Educacion y Ciencia of Spain, the Ellinson Medical Foundation, the American Federation for Aging Research and the American Diabetes Association.
Authors on the paper are Lerin, Joseph Rodgers, Dario Kalume, Seung-hee Kim, Akhilesh Pandey, and Puigserver, all of Hopkins.
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Journal
Cell Metabolism