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NUTRITION Macrophage Protein May Block AtherosclerosisLinks Heart Disease to Insulin Resistance and Diabetes Forget about exercise. Abandon your low-fat diet. Pull up a couch, turn on the TV, and unwrap that burger. Imagine being able to wallow in the modern American lifestyle without having to pay the price later in heart disease and diabetes.
A new study from the laboratory of Gokhan Hötamisligil identifies a protein in immune cells that appears to transform a diet high in fat and cholesterol into clogged arteries. Mice missing the gene that makes the protein in macrophage cells were protected from atherosclerosis. Photo by Graham Ramsay It's still a fantasy for people, but certain laboratory mice are living this dream. HSPH researchers have created a mouse that can indulge in the murine equivalent of a fast-food diet—as reflected by dangerously high cholesterol levels—and yet remain protected from atherosclerosis. The experience of these protected mice shows that a protein named for its role in fat cells, where it helps dietary obesity cause insulin resistance and diabetes, also appears to work in immune cells to transform a high-fat diet and high cholesterol into clogged arteries. A new study in the June Nature Medicine identifies this adipocyte fatty-acid–binding protein, aP2, in macrophages as a novel potential molecular target to prevent and treat coronary heart disease, the number one killer in this country. The latest revelation about aP2 comes from a collaboration between the laboratories of Gokhan Hötamisligil, HSPH associate professor of nutrition, and MacRae Linton, associate professor of medicine and pharmacology at Vanderbilt University School of Medicine. The work was supported in part by the National Institutes of Health. Syndrome XThe newly discovered mechanism in macrophage cells also provides another tantalizing molecular link in a cluster of major risk factors that has come to be known as "metabolic syndrome." Also known as syndrome X, it is closely related to insulin resistance and includes obesity, heart disease, atherosclerosis and Type II diabetes. By one estimate, metabolic syndrome affects one quarter of all middle-aged U.S. adults. More than half of the people in this country will suffer one of the syndrome X components. Obesity is the main factor, but the syndrome is diagnosed by three or more of these symptoms: large waist, high triglycerides, low high-density lipoprotein, elevated blood pressure, and elevated fasting glucose, according to the new cholesterol guidelines released in May by the National Institutes of Health.Encoded by the gene Ap2, the protein belongs to a family of small molecules housed in the cell's cytoplasm. Different tissues express different family members; aP2 is expressed mainly in adipose tissue and, as shown by these experiments, in macrophages. Scientists believe aP2 and other fatty-acid–binding proteins facilitate the transport of triglycerides and low-density lipoproteins from the circulating blood into the cells. Inside the cells, fatty-acid–binding proteins grab the lipids and other lipid byproducts and hand-deliver them to the nucleus, mitochondria, and other intracellular targets, which in turn generates a range of responses leading to insulin resistance, diabetes, or heart disease. "What is fascinating is the functional and mechanistic overlaps defined by aP2 between the fat cells and macrophages in lipid handling," Hötamisligil said. Mounting PlaqueFive years ago, Hötamisligil showed that aP2 was necessary in mice for fat cells to orchestrate the metabolic processes that turn obesity into insulin resistance or diabetes. Now, in an effort led by HSPH graduate student Liza Makowski, macrophages appear to need aP2 to release a battery of cytokine troops to mediate the inflammatory response of atherosclerotic disease. The protein aP2 also appears to stimulate the macrophages to gobble up cholesterol and other lipids to make the characteristic foam cells composing atherosclerotic plaque."These rather surprising findings offer new insights into how systemic and cellular lipid metabolism is linked to inflammatory response," Hötamisligil said. In the first set of experiments, the researchers used mice developed in Hötamisligil's lab that were deficient in aP2 as well as apolipoprotein E (apoE), a protein involved in removing cholesterol and fat from the blood. Deleting only apoE allowed cholesterol to remain in the mouse blood at very high levels, resulting in severe atherosclerosis. However, when aP2 was also missing, these mice exhibited minimal signs of disease, showing as much as 87 percent less blockage in arteries of the males compared to the controls. These mice lacked aP2 in both adipocytes and macrophages. The researchers next focused on the contribution of each cell type to the observed pathologies. A second set of experiments teased out the independent contribution of aP2 in macrophages, distinct from aP2 in adipocytes. The protein is expressed in activated macrophages, but not in other bone marrow–derived cells. So the Vanderbilt team transplanted bone marrow from aP2-deficient mice to apoE-deficient mice. The resulting animals, missing aP2 only in their macrophages but not in other cells, showed significant protection against atherosclerosis, with none of the distinct glucose and lipid metabolism differences caused by aP2 in fat cells. The researchers are following up with studies to address more directly the actual mechanism of why Ap2 gene expression by macrophages seems to promote foam cell formation. —Carol Cruzan Morton |
