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U Health Scientists Reverse Prediabetes in Mice

SALT LAKE CITY, UT — University of Utah graduate student Trevor Tippetts of Irving was among a group of scientists from U Health and Merck Reserach Laboratories that led research that determined how a small chemical change makes the difference between mice that are healthy and mice with insulin resistance and fatty liver, major risk factors for diabetes and heart disease. Making the change prevented the onset of these symptoms in mice fed a high-fat diet and reversed prediabetes in obese mice.

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 the 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.

“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,” Scott Summers, chair of nutrition and integrative physiology at U of U Health, said. “Our work shows ceramides have an influential role in metabolic health. We’re thinking of ceramides as the next cholesterol.”

Although the impact of lowering ceramides in humans is still unknown, there is evidence ceramides are linked to metabolic disease, Summers said. He points out that clinics are already performing ceramide screening tests to gauge an individual’s risk for developing heart disease.

Summers and David Kelley, co-senior author on the study, are now developing drugs that inhibit DES1 with a goal of making new therapeutics.

“This project provides substantial validation that this is a discreet and highly effective point of intervention,” Kelley said.

If ceramides cause poor health, why do we have them in the first place? Summers’ group addressed the question by measuring how the lipid affects metabolism. They found ceramides trigger a number of mechanisms that promote the storage of fat in cells. They also impair cells’ ability to use glucose, a type of sugar, as fuel.

The evidence for these effects includes activation of a molecular pathway, Akt/PKB, that inhibits both the ability of cells to synthesize sugars and to take them up from the bloodstream. At the same time, ceramides slow the turnover of fatty acids in part by causing cells in the liver to increase fatty acid storage and adipose tissue to burn less fat.

The shift in how cells use fuel is an advantage in the short-term, Summers said. This is because ceramides have another role in stiffening the cell membrane and promoting fat storage increases production of ceramides. These data suggest one benefit of ceramides is to protect the cell. When food is plentiful and cells engorge with fat, increasing ceramide levels strengthens the cells’ outer membrane, preventing ruptures.

“Serving in this role is usually good but it can potentially be bad,” Tippetts, a graduate student in Summers’ lab, said. He, U of U Health research assistant professor Bhagirath Chaurasia, and two of their Merck colleagues, Rafael Mayoral Monibas, and Jinqi Liu, share lead authorship.

Tippetts explains that problems arise in times of chronic overabundance, such as during obesity, when there are persistently high levels of ceramides. The sustained shift toward fat storage and away from using sugar as fuel leads to fatty liver disease and insulin resistance.

“We think our results are telling us that ceramides evolved to become a nutritional sensor,” Chaurasia said. Ceramides serve as a signal, helping the body to cope when the amount of fat coming into cells exceeds energetic needs and storage capacity.

These findings are leading to a deep understanding of how cells in the body assess nutrient status and adjust their behavior accordingly.

SOURCE University of Utah