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Drug Development

Blocking an enzyme keeps mice from getting diabetes

Inhibitors to the enzyme DES1 could be a new class of metabolic syndrome drugs

by Megha Satyanarayana
July 11, 2019 | APPEARED IN VOLUME 97, ISSUE 28

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Blocking the formation of the double bond in the backbone of ceramide seems to prevent metabolic syndrome in mice

New research suggests that compounds that block the formation of lipids called ceramides could represent a novel class of drugs to prevent diabetes and metabolic syndrome. The approach shows promise in mice.

Ceramides are an important component of cell membranes, creating stable structures to promote cell signaling. These molecules, made of sphingosine backbones and variable-length chains of fatty acids, also have a role in nutrition, says Scott Summers, the University of Utah researcher who led the work. When we eat fat, cells store some of it as triglycerides, but also burn some of it through the mitochondria. Yet, previous research has shown that when we take in more fat than our cells can handle, some of the leftover fatty acids get shunted into a ceramide-forming pathway. Excess ceramides interfere with metabolic pathways, including those based on glucose and fat. In excess, ceramides can be “pretty bad for you,” Summers says.

To figure out how to break down excessive ceramides, Summers’ group started looking at the multistep process by which they are made. One enzyme involved is dihydroceramide desaturase-1 (DES1), which sticks a double bond between positions 4 and 5 in the sphingoid part of the molecule. The researchers knocked down DES1 expression in the liver and fat tissues of adult mice. Compared to controls, treated animals metabolized glucose better, suggesting healthier metabolism and a lower risk of developing cardiovascular disease, diabetes, and other metabolic syndromes (Science 2019, DOI: 10.1126/science.aav3722).

The team also tried to mimic the human habits of overeating and weight gain that often leads to metabolic syndrome in their mouse models. Through genetic engineering, Summers’ team removed DES1 in mice that lacked leptin, a hormone that controls satiety, or removed DES1 in mice fed a high-fat diet. In either case, the mice did not gain as much weight as controls, made less ceramide, and were better able to metabolize glucose. Having less ceramide didn’t seem to affect the animals’ overall health.

Summer has cofounded a company called Centaurus Therapeutics, whose lead compound targets DES1. Jeremy Blitzer, the company’s chief scientific officer, says they hope to have it in clinical trials in 18 months.

The work defies a long-standing idea in the field, says Richard Kolesnick, a sphingolipid researcher at Memorial Sloan Kettering Cancer Center. As with “good” cholesterol and “bad” cholesterol, there is an idea that ceramides of one length are deleterious and ceramides of another are not. This idea is the basis of a Mayo Clinic test that measures ratios of ceramides of different lengths in order to predict whether someone will develop metabolic syndrome. But the mouse studies seem to suggest that reducing any ceramide species is helpful in preventing metabolic syndrome.

The ratio of ceramide to dihydroceramide might be the basis of a new predictive test, Kolesnick says. Blitzer says Centaurus Therapeutics uses such ratios as part of their pharmacodynamics profiling of their lead candidate, which is still being tested in animals.

Kolesnick says DES1 holds some promise as a drug target, “It’s certainly a different way of thinking about approaching diabetes compared to insulin and glucose therapies.”

Many metabolic pathways are being targeted in the development of drugs for metabolic syndrome. Summers says previous experiments done by his lab and others suggest that DES1 may be a safer target than other enzymes in the pathway.

Christopher Newgard, a metabolic physiology expert at Duke University agrees, but notes that metabolic syndrome is complex, covering many organs and several signaling pathways that are not addressed in Summers’ work. But Summers’ results make Newgard optimistic about new ways to approach the syndrome.

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