Cleveland Researchers Discover Enzyme That Controls Both Weight Gain and Cholesterol Levels in Animal Models

New Study from University Hospitals and Case Western Reserve University published in Science Signaling

• Rates of obesity and associated fatty liver disease have risen as the world increasingly adopts energy-dense diets and sedentary lifestyles.
• Cleveland research team has discovered a new enzyme that is required to make fat.
• Blocking the enzyme prevented weight gain and lowered cholesterol.
• A three-in-one drug is being developed to treat obesity, fatty liver disease, and cardiovascular disease.
  

CLEVELAND -Obesity is a global epidemic and a major cause of morbidity and mortality because it increases the risk for comorbidities, including heart disease and fatty liver disease (MASLD). Rates of these disorders have risen as the world increasingly adopts energy-dense diets and sedentary lifestyles.

Nitric oxide is a gas molecule with pleiotropic actions in the body. These effects of nitric oxide are carried out through its binding to proteins. Too much or too little nitric oxide binding (to key proteins) causes disease.

In a new study, published December 23^rd in the AAAS journal, Science Signaling, a research team from University Hospitals and Case Western Reserve University discovered a novel enzyme (SCoR2) that removes nitric oxide from proteins controlling fat build up. Removal of nitric oxide turned on fat synthesis, establishing that SCoR2 is needed to make fat.

The team then inhibited SCoR2 genetically and by developing a drug. They found that blocking this nitric oxide-removing enzyme prevented weight gain and liver injury in mouse models. The same drug also lowered bad cholesterol.

"We have a new class of drug that prevents weight gain and lowers cholesterol-a potential therapy for obesity and cardiovascular disease, with additional hepatic benefits," explained lead author of the study, Jonathan Stamler, MD, President and Co-Founder, Harrington Discovery Institute, Distinguished University Professor, Robert S. and Sylvia K. Reitman Family Foundation Professor of Cardiovascular Innovation, and Professor of Medicine and of Biochemistry at University Hospitals and Case Western Reserve University.

"In the liver, nitric oxide inhibits the proteins that make fat and cholesterol. In fat tissue, nitric oxide inhibits the genetic program that makes the enzymes that create fat," Dr. Stamler added.

Next steps in this research involve advancing the drug into clinical trials, which should take about 18 months.

"Our team looks forward to further developing a first-in-class drug to block weight gain and lower cholesterol, with favorable effects on liver health," Dr. Stamler said.

The drug will be developed with the help of Harrington Discovery Institute at UH, which has a singular mission: To accelerate promising discoveries into medicines for unmet needs. Now in its 13^th year, Harrington Discovery Institute'sgrowing portfolio includes 227 medicines in the making; 75 institutions supported; 46 companies launched; 24 medicines in clinic; and 15 licenses to pharma.

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Venetos, Nicholas M., et al."The protein denitrosylase SCoR2 regulates lipogenesis and fat storage." Science Signaling.DOI: 10.1126/scisignal.adv0660