Cellular Fat Sensor Slows Heart Disease

The study, which appears in the Oct. 17 edition of Science and is posted on the journal's web site, uncovers a unique pathway that significantly curbs the development of atherosclerosis - the accumulation of fatty deposits on arterial walls. The pathway could be used to develop drugs to treat heart disease, currently the number one killer of Americans.

Ronald Evans, the March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute, research fellow Chih-Hao Lee and colleagues found that the regulatory molecule, PPAR-delta (short for peroxisome proliferator-activated receptor), plays a powerful part in the body's inflammatory response to the beginning phases of atherosclerosis.

"Immune cells promote inflammation, which stimulates the transport and absorption of fat that triggers the early stages of heart disease," Evans said. "Our study uncovered the molecular switch that regulates this process and reveals how the inflammatory response, designed to fend off invading agents, can go awry and encourage atherosclerosis and heart disease."

The researchers found that the PPAR-delta switch cut heart disease in half. It does this by disrupting a cellular signal that controls the inflammatory response.

Activation of PPAR-delta by a fat-like drug reduces inflammation and discourages the growth of atherosclerotic plaques.

"The lesions that cause atherosclerosis are very complex, and are aggravated," said Evans. "We believe that PPAR-delta normally acts as a molecular soldier to guard against inflammation and disease. Unfortunately, these good effects are compromised by high fat diets, poor exercise, infections and stress. Chemicals that regulate the activity of PPAR-delta could form the basis of a new drug to reduce atherosclerosis and therefore be a possible therapy for heart disease."

Heart disease is the number one health threat to Americans; about one million die from some form of heart disease every year. The Howard Hughes Medical Institute and the National Heart Lung and Blood Institute supported the researchers' work. Evans' collaborators at the Scripps Research Institute include Drs. Linda Curtiss and William Boisvert.

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The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. Jonas Salk, M.D., founded the institute in 1960 with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.