Cleveland researchers discover enzyme that controls both weight gain and cholesterol levels in animal models

• 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’s growing 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

About University Hospitals / Cleveland, Ohio
Founded in 1866, University Hospitals serves the needs of patients through an integrated network of more than 20 hospitals (including 5 joint ventures), more than 50 health centers and outpatient facilities, and over 200 physician offices in 16 counties throughout northern Ohio. The system’s flagship quaternary care, academic medical center, University Hospitals Cleveland Medical Center, is affiliated with Case Western Reserve University School of Medicine, NEOMED, Oxford University, Technion Israel Institute of Technology, and National Taiwan University College of Medicine. The main campus also includes the UH Rainbow Babies & Children's Hospital, ranked among the top children’s hospitals in the nation; UH MacDonald Women's Hospital, Ohio's only hospital for women; and UH Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the most prestigious clinical and research programs in the nation, with more than 3,400 active clinical trials and research studies underway. UH Cleveland Medical Center is perennially among the highest performers in national and international ranking surveys, including “America’s Best Hospitals” from U.S. News & World Report and UK Brand Finance. UH is also home to 19 Clinical Care Delivery and Research Institutes. UH is one of the largest employers in Northeast Ohio with more than 30,000 employees. Follow UH on LinkedIn, Facebook and Twitter. For more information, visit UHhospitals.org.

About Case Western Reserve University
As one of the fastest-growing research universities in the United States, Case Western Reserve University is a force in career-defining education and life-changing research. Across our campus, more than 12,000 students from around the world converge to seek knowledge, find solutions and accelerate their impact. They learn from and collaborate with faculty members renowned for expertise in medicine, engineering, science, law, management, dental medicine, nursing, social work, and the arts. And with our location in Cleveland, Ohio—a hub of cultural, business and healthcare activity—our students gain unparalleled access to academic, research, clinical and entrepreneurial opportunities that prepare them to join our network of more than 125,000 alumni worldwide. Visit case.edu to see why Case Western Reserve University is built for those driven to be a force in the world.

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