Merck Research Laboratories and the University of Utah Health have shown that deactivation of the dihydroceramide desaturase 1 (DES1) enzyme could offer a potential drug target for metabolic diabetes.
The researchers prevented the enzyme from removing hydrogens from a fatty lipid known as ceramide that is believed to be related to metabolic health.
In mice fed with a high-fat diet, enzyme deactivation was observed to prevent the onset of insulin resistance and fatty liver, which are both signs of metabolic disease. In this way, the change reversed prediabetes in obese mice.
It is expected that DES1 will provide a druggable target for treatments of metabolic disorders such asprediabetes, diabetes and heart disease.
The University of Utah health, nutrition and integrative physiology chair Scott Summers said:
We have identified a potential therapeutic strategy that is remarkably effective, and underscores how complex biological systems can be deeply affected by a subtle change in chemistry. Our work shows that ceramides have an influential role in metabolic health. We’re thinking of ceramides as the next cholesterol.
During the research, the team used two approaches to block the last step of ceramide synthesis. The scientists genetically engineered mice to switch off the gene coding for DES1 during adulthood and deactivated the gene from all body tissues.
As part of the second approach, they injected short hairpin ribonucleic acid (RNA) into the adult liver in order to selectively lower DES1 production by destroying the RNA precursor.
To assess the approaches, the group initially fed adult mice with a high-fat diet, causing the animals to gain excess weight and lead to the development of insulin resistance and fatty liver.
Within weeks of minimising ceramide levels using either of the new approaches, significant changes were observed in the animals’ metabolic health. Mice remained obese but the fat was cleared from their liver and they responded to insulin and glucose normally.
Another test demonstrated that lowering ceramides prior to putting the mice on a high-fat diet could prevent weight gain and insulin resistance.
Researchers are currently evaluating the long-term effects of chemical changes on health and developing DES1 inhibitors as potential new drugs.