The study, led by New York University School of Medicine researcher Edward A. Fisher, MD, PhD, the Leon H. Charney Professor of Cardiovascular Medicine and Professor of Cell Biology, is published in the May issue of the Journal of Clinical Investigation.
"It does appear that antioxidant vitamins may be potentially harmful for the heart based on their ability to increase the secretion of VLDL in the liver cells and in the mice that we studied," says Dr. Fisher, who directs the Lipid Treatment & Research Center at NYU Medical Center.
After its secretion from the liver, VLDL is converted in the bloodstream to low-density lipoprotein (LDL), the so-called bad form of cholesterol. The liver is the major source of atherosclerosis-causing lipoproteins. "However, our study is the first to document this association between antioxidant vitamins and VLDL cholesterol, and more studies are needed to back up our findings," says Dr. Fisher, who is also Director of the Marc and Ruti Bell Vascular Biology and Disease Research Program at NYU.
"Until more data becomes available, we can't make any recommendations about whether people should not use these vitamins," says Dr. Fisher.
Overall, antioxidants usually have been considered healthful. The vitamins scavenge "free radicals," which are highly reactive and damaging forms of oxygen produced by natural metabolic processes in the body and by external sources like the sun's UV rays, ozone, and toxins in pesticides, among other things. In the early 1990s, laboratory studies suggested that antioxidant vitamins prevented biochemical changes that made cholesterol form plaques that can block blood flow through the arteries. Although some subsequent clinical studies seemed to back up these findings, others did not.
The new study by Dr. Fisher and his colleagues provides a different perspective on antioxidants. Surprisingly, his group found that antioxidants hampered a process in the liver that prevents the production of harmful lipoproteins.
When cells are under "oxidative stress," free radicals produced by the normal conversion of polyunsaturated fatty acids to lipid peroxides bombard the cells. The scientists discovered that liver cells respond by activating a pathway that breaks down ApoB100, a critical protein component of VLDL and other harmful lipoproteins. Deprived of the ApoB, the liver cannot now produce these bad lipoproteins and their secretion into the bloodstream is reduced substantially.
In further experiments, vitamin E, a well-known antioxidant, prevented the activation of the lipoprotein-breakdown pathway in rat and mouse liver cells. Thus, the liver destroyed fewer of the bad lipoproteins.
The study also explains why polyunsaturated fatty acids, the good fatty acids found in cold water fish, are healthy for the heart. In another series of experiments, the scientists show that omega-3 and omega-6 fatty acids activated the pathway in the liver that breaks down the bad lipoproteins. Dr. Fisher's group recently described this pathway, which they dubbed PERPP for post-ER presecretory proteolysis.
The scientists also found that the polyunsaturated fatty acids increased the generation of lipid peroxidation products (these compounds produce the nasty smell of rancid fish) and stimulated the PERPP pathway. In addition to the studies with liver cells in laboratory dishes, they also demonstrated the relationship between lipid peroxidation and reduced production of bad lipoproteins in living mice.
Dr. Fisher plans to conduct further experiments in mice to confirm these findings. Direct experimentation in people to explore the inner workings of the liver is difficult, says Dr. Fisher, "but there are already observational studies in normal people showing that a diet enriched in polyunsaturated fats increases blood levels of lipid peroxides and decreases levels of VLDL and LDL."
Antioxidants may still have beneficial affects on other parts of the body, says Dr. Fisher. The molecules, for example, have been shown in some animal studies to protect the arteries from atherosclerosis and the pancreas and other organs from damage caused by diabetes. "In other words, oxidant stress is damaging in some contexts, but probably beneficial in others," he says. "In terms of the risk of cardiovascular disease," he adds, "the previous view that all oxidant stress is bad is probably an oversimplification."
In an editorial accompanying the study titled "Hold the antioxidants and improve plasma lipids?," Ronald Krauss of Children's Hospital Oakland Research Institute in California, writes, "Thus, although there is considerable evidence for the involvement of oxidative stress in many disease processes, including atherosclerosis, the potential for unintended outcomes of oxidant therapy should serve as a warning against proceeding with such treatment in the absence of clinical-trial evidence of benefit and safety."
The new study was supported by grants from the National Institutes of Health and the American Diabetes Association.
Dr. Fisher's co-authors on the study are: Meihui Pan of NYU School of Medicine; Arthur Cederbaum of Mount Sinai School of Medicine, New York; Yuan-Li Zhang and Henry Ginsberg of the College of Physicians and Surgeons, Columbia University, New York; and Kevin Jon Williams of Jefferson Medical College, Thomas Jefferson University, Philadelphia.