Switching off this enzyme reversed prediabetes in mice

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Targeting the body’s ceramide chemistry in a subtle way could lead to the development of safe new treatments for type 2 diabetes, heart disease, and other metabolic conditions.
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Scientists have reversed prediabetes by switching off a certain enzyme.

This was the suggestion that scientists made after finding that they could reverse prediabetes in mice with obesity by silencing an enzyme responsible for the final step of ceramide production.

Deactivating the enzyme, called dihydroceramide desaturase 1 (DES1), lowered levels of ceramide in the body, they note in a recent Science paper about their work.

Switching off DES1 also prevented mice on a high fat diet from developing fatty liver and insulin resistance. These two conditions are prime risk factors for heart disease and diabetes.

DES1 controls the conversion of dihydroceramide into ceramide with a small chemical shift of two hydrogen atoms. This subtle alteration effectively inserts a “double bond into the backbone” of the lipid molecule.

Previous investigations had already suggested that reducing ceramide levels could potentially reverse metabolic disease and diabetes. However, the methods that they used would result in severe side effects.

‘Ceramides as the next cholesterol’

The new study takes the research in a more promising therapeutic direction. It suggests that it could be possible to reduce ceramide levels in a safe way with a small, well timed tweak to the process of ceramide production.

“Our work,” says co-senior study author Prof. Scott A. Summers, department chair of Nutrition and Integrative Physiology at the University of Utah in Salt Lake City, “shows that ceramides have an influential role in metabolic health.”

“We’re thinking of ceramides as the next cholesterol,” he adds.

Scientists are still finding out how lowering the ceramides affects the body. However, there is evidence, Prof. Summers argues, of a link between ceramides and metabolic disease.

He says that some doctors are already carrying out tests of ceramide levels as a way to assess people’s risk for heart disease.

“Ceramides contribute to the lipotoxicity that underlies diabetes, hepatic steatosis [fatty liver], and heart disease,” note the authors of the new study.

If ceramides can be a cause of disease, what purpose do they serve in the body? The researchers investigated this question by assessing the impact of ceramide on metabolism.

Ceramide pros and cons

In a 2013 study into DES1 and ceramides, Prof. Summers and his co-authors discussed how obesity could increase metabolic disease risk, and how ceramides contribute.

The theory is that in people with obesity, the body’s tissues receive an abundance of lipids that they cannot store, and this leads to a buildup of “fat-derived molecules that impair tissue function.”

Prof. Summers and his colleagues discovered that ceramides set off a number of processes that increase fat storage in cells. In addition, they disrupt the ability of cells to get energy from sugar, or glucose.

The lipids also slow down the processing of fatty acids. They do this in two ways: by getting the liver to store more fatty acids, and by reducing fat burning in tissues.

Ceramides also have other functions. One of these is to strengthen cell walls.

Prof. Summers therefore suggests that because increasing fat storage raises ceramide levels, it would seem that ceramides have a role in protecting cells from rupturing during times of plenty, when the body increases its fat stores.

However, in the case of obesity, ceramide appears to take on the role of a toxic lipid.

Obese mice had improved metabolic health

In the recent study, the researchers lowered ceramide levels in mice by shutting off the last step of ceramide synthesis. To accomplish this, they genetically engineered mice in which they could switch off the gene for DES1 in adult animals.

They developed two ways of switching off DES1: globally and selectively. In the global approach, they silenced DES1 in the whole body. In the selective approach, they switched off the enzyme in selective locations, such as in the liver or fat cells.

When they switched off DES1 to lower ceramides in extremely obese mice with insulin resistance and fatty liver, they found that either approach worked. The animals’ metabolic health improved, even though they remained obese.

Their livers got rid of fat, and their insulin and glucose responses were as sharp as those of healthy, lean mice. After 2 months of observation, the animals remained in good health.

Prof. Summers explains that although the mice did not shed any weight, their bodies had changed the way that they processed nutrients.

In another set of experiments, the team found that reducing ceramide levels before placing the mice on high fat diets stopped the animals from gaining weight and developing insulin resistance.

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.”

Prof. Scott A. Summers

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