A nuclear receptor protein, known for controlling the ability of cells to burn fat, also exerts powerful anti-inflammatory effects in arteries, suppressing atherosclerosis in mice prone to developing the harmful plaques, according to new research by scientists at the Salk Institute for Biological Studies and the Harvard School of Public Health.
Their findings, reported in this week's online edition of the Proceedings of the National Academy of Sciences, offer a new and specific target for the development of drugs that specifically treat cardiovascular complications associated with metabolic syndrome.
“Heart disease is like a ticking clock - it is progressive, relentlessly marching forward accelerated by a mix of high fat diets, inflammation and high blood pressure. We show that PPAR delta offers a kind of genetic shortcut around each of these medical roadblocks,” says Howard Hughes Medical Investigator Ronald M. Evans, Ph.D., a professor in the Salk Institute's Gene Expression Laboratory, who co-directed the study with Chih-Hao Lee, a professor in the Department of Genetics and Complex Diseases at the Harvard School of Public Health.
“Most people believe cholesterol plays a predominant role in atherosclerosis. Our study suggests that targeting inflammation at lesion sites is just as important,” adds Lee.
Like the Yin and Yang of fat metabolism, PPAR delta - the focus of the current study - and its counterpart PPAR gamma control the storage and burning of fat. PPAR gamma is in charge of storing surplus glucose as fat. When PPAR gamma is stimulated by a drug the body's response to insulin improves, lowering levels of circulating glucose. Its sibling gene switch, PPAR delta, controls the ability of cells to burn fat. Activating PPAR delta revs up the fat-burning capacity of adipose tissue and muscle, dramatically lowers overall body weight, increases HDL (“the good cholesterol”), reduces circulating triglycerides, and improves hyperglycemia.
“Cardiovascular disease is a leading cause of death in patients with metabolic syndrome, a clustering of obesity-related disorders including insulin resistance, hypertension, and dyslipidemia,” says postdoctoral researcher and first author Grant D. Barish, M.D. “Since PPAR delta plays a key role in fat metabolism and PPAR delta drugs can protect against obesity, we wanted to know whether activating PPAR delta would protect against atherosclerosis.”