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Early study reveals ‘nuclear’ strategy for atherosclerosis

Apr. 18, 2013, 9:42 AM

Vanderbilt University scientists have discovered a potential new strategy for lowering cholesterol and triglyceride levels and stopping atherosclerosis and fatty liver disease.

Reporting this month in the Journal of the American Heart Association, the researchers showed in a mouse model that they could interrupt the cascade of intracellular events that lead to cholesterol and fatty acid synthesis as well as inflammation in the liver.

They designed and used a custom-made, cell-penetrating peptide (protein fragment) to keep other proteins called transcription factors from entering the nucleus and turning on genes responsible for the inflammatory and metabolic underpinnings of heart disease.

The result was striking, said Jacek Hawiger, M.D., Ph.D., who with Robert Collins, M.D., professor of Pathology, Microbiology and Immunology, was co-senior author of the report.

They collaborated with Amy Major, Ph.D., assistant professor of Medicine in the Division of Cardiovascular Medicine.

Following treatment with the peptide, called a Nuclear Transport Modifier because it modifies or modulates transport into the nucleus, blood cholesterol, triglyceride and glucose levels of mice that had been fed a high-fat Western diet were significantly lower than in control animals.

The development of atherosclerosis — fatty deposits — in the aorta was suppressed. Accumulated fat was also cleared from the liver while liver inflammation was “extinguished.”

“Moreover,” said Hawiger, “weight gain was prevented without reducing food intake.”
To sum it up, an eight-week treatment with this “first-in-class” peptide significantly improved lipid profile and metabolism in the mice “from a grossly deranged state,” and with no observed adverse effects, he said.

Of course, these preclinical studies await translation into potential clinical applications to human diseases, said Hawiger, Distinguished Professor of Medicine, Louise B. McGavock Chair in Medicine and professor of Molecular Physiology and Biophysics.

Nevertheless, the researchers concluded, “a new strategy for the comprehensive reduction of metabolic inflammation has emerged.”

Hawiger, Collins and Majors’ co-first authors were Yan Liu, M.D., and Jozef Zienkiewicz, Ph.D., joined by Curtis Gabriel, Ph.D., Ruth Ann Veach, B.S., and Daniel Moore, M.D., Ph.D.

The research was supported in part by National Institutes of Health grants HL085833, AA015752, HL088364, HL089310, DK090146, CTSA award TR000445 and the Vanderbilt Immunotherapy Program.

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