Posted by 
The scientists changed the trajectory of metabolic disease by deactivating an enzyme called dihydroceramide desaturase 1 (DES1). Doing so stopped the enzyme from removing the final hydrogens from a fatty lipid called ceramide, having an effect of lowering the total amount of ceramides in the body.
The finding highlights a role for ceramides in metabolic health and pinpoints DES1 as a “druggable” target that could be used to develop new therapies for metabolic disorders such as prediabetes, diabetes and heart disease—that affect the health of hundreds of millions of Americans. Scientists at University of Utah Health and Merck Research Laboratories led the research, published online in Science on July 4, 2019.
“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,” says Scott Summers, Ph.D., chair of Nutrition and Integrative Physiology at U of U Health, who was co-senior author on the study with David Kelley, M.D., formerly of Merck Research Laboratories.
“Our work shows that ceramides have an influential role in metabolic health,” says Summers. “We’re thinking of ceramides as the next cholesterol.”
This isn’t the first time that Summers’ group has found that lowering ceramides could reverse signs of diabetes and metabolic disease. However, techniques used in previous experiments caused severe side effects, showing the approach would not be suitable for therapeutic applications.
This time, rather than taking a sledgehammer to the problem, they developed a fine scalpel. They wondered whether making the smallest change possible and at a precise time and place might yield better results.
To lower ceramides, the investigators blocked the final step of ceramide synthesis in two ways. Summers’ group genetically engineered mice in which the gene coding for DES1 could be switched off during adulthood and deactivated the gene from tissues throughout the body, or alternatively from either liver or fat cells. Kelley’s group injected short hairpin RNA into the adult liver, a method that selectively lowered production of DES1 by destroying the RNA precursor.