DHPS is a conserved protein that it is found in many different animal species from bacteria to humans. It has mostly been studied in yeast and other cultured cells but its role in inflammation or obesity is unknown.
“When I joined the lab as a postdoc, I was interested to see if the DHS pathway could be a common thread promoting inflammation both in the pancreas, as Dr. Mirmira’s lab had shown, and in the setting of adipose tissue meta-inflammation,” said Emily Anderson-Baucum, PhD, a former postdoctoral scholar at Indiana University.
The researchers focused on the downstream effects on the e1F5A protein, which DHPS activates by modifying a lysine amino acid to generate a rare amino acid called hypusine.
ElF5A is important in the production of other proteins because of its effects on mRNA translation, but it only does this when cells are under stress. This is actually protective, but a protective process can become destructive if the stress is ongoing, and can eventually kill the cell.
Obesity is an example of an environment that tends to put a lot of stress on our cells, which can trigger these inflammatory pathways that normally would not be triggered.
Researchers found that in mice that were fed a high-fat diet and became obese, there was an increase in the expression of DHPS, and the activated form of elF5A elF5AHyp enriched in macrophages found in adipose tissue.
Macrophages, a type of white blood cell that play a role in the immune system by disposing foreign and dead cells. Increased expression of elF5AHyp led to an increase in the number of inflammatory macrophages.
When they blocked this enzyme, the way macrophages behaved changed. Even obese animals did not exhibit metabolic dysfunction, and hyperglycemia (high blood glucose).
These results are strong evidence that macrophages are crucial for the development of the inflammation seen in obesity. Addressing this inflammation can be a key component of treating obesity and its complications.
The next step will be to understand the complete pathway, including the DHPS enzyme and elF5A, and to see if it is possible to develop a small molecule that is capable of blocking the DHPS enzyme in humans.
People can view obesity as an issue of poor choices, but it is more complicated than that. There are genetic and environmental factors involved. This study shows us that not all of the consequences of obesity are inevitable.
Finding good ways to control blood sugar and treat diabetes will be important for the population and for the healthcare system.