At last!
Arbor
Public release date: 3-May-2004 Contact: Jennifer Berman
[email hidden] 212-404-3555 New York University
Medical Center and School of Medicine
Could vitamins raise levels of bad cholesterol? Animal study
suggests they might The notion that antioxidant vitamins
could provide a safe, convenient way to protect the heart
from disease appears to have hit a pothole. Instead of
protecting the heart, a new study suggests that the
vitamins, such as E, C, and beta carotene, could raise the
production by the liver of the so-called bad form of
cholesterol, which transports cholesterol into artery walls.
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.
Ds. 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