The cholesterol conundrum
The tricky balance between “good” and “bad” lipids
It’s a crucial component of our cell membranes. It helps prevent the diffusion of small water-soluble molecules into the cell, and keeps membranes fluid enough to maintain their firm, but pliable, consistency.
A sterol molecule, cholesterol also is the precursor for steroid hormones like estrogen, testosterone and cortisol, which are important for reproduction, metabolism, immune function and stress responses.
What gives cholesterol either a “bad” or “good” reputation is the company it keeps—the lipoproteins that transport it through the body.
Lipoproteins are made by both the intestine and the liver and contain cholesterol, triglycerides and proteins. Triglycerides are the primary means by which the body transports and stores fatty acids, the basic unit of fat that our cells burn for energy.
High-density lipoprotein (HDL) is considered to be “good,” because it carts excess cholesterol off to the liver, where it is excreted in bile. Low-density lipoprotein (LDL), on the other hand, contributes to atherosclerosis.
LDL begins as a very low density lipoprotein (VLDL) produced in the liver. VLDL can be broken down in the bloodstream into fatty acids to provide an immediate source of fuel, and it also transports triglycerides to fat cells for later use.
In either case, after giving up its cargo of fat, VLDL becomes LDL, which then transports cholesterol to peripheral tissues. In some tissues like the skin, accumulation of cholesterol is inconsequential. The problem starts when cholesterol builds up along artery walls.
“For the same reason you don’t want too much calcium in your water, you don’t want too much LDL in your plasma—because your pipes will get encrusted,” says Sergio Fazio, M.D., Ph.D., who co-directs the Atherosclerosis Research Unit at Vanderbilt University Medical Center with MacRae F. Linton, M.D.
The artery wall doesn’t like the accumulation of cholesterol, and recruits cells from the blood, mainly macrophages, to try to clean it up. These macrophages become engorged with cholesterol, and are known as “foam cells” due to their bubbly appearance.
“What starts with good intentions as a clean-up effort, ends up creating more of a mess,” Fazio explains. Atherosclerotic plaques are simply “big conglomerates of cells enriched with cholesterol.”
Diet and exercise can be very effective in lowering LDL levels, and can significantly reduce the risk of heart disease.
“We know what a healthy diet and lifestyle are,” says Linton, who has collaborated with Fazio since the early 1990s. “If you could wave a magic wand to get everyone in the country to live that way, you could eliminate—or at least dramatically reduce—the incidence of coronary disease and diabetes.
“The real problem,” he adds, “is it is hard to change people’s lifestyles.”
As a result, many patients and their doctors have turned to statins, a class of LDL-lowering drugs that have been shown to reduce the risk of heart attack and stroke by 30 percent to 40 percent.
Statins, however, are not without side effects, and many patients on the drugs still suffer adverse cardiovascular events—heart attack, stroke, and sudden cardiac death.
An attempt to “ramp up” this process, however, was halted last year when it appeared that an HDL-raising drug, torcetrapib, increased rather than decreased the incidence of heart-related deaths in a clinical trial.
The drug significantly increased HDL levels by blocking an enzyme that normally transfers cholesterol from HDL to LDL, but it failed to slow the progression of atherosclerosis as expected.
Fortunately, there are other ways to raise HDL levels.
One possibility is niacin, a vitamin supplement available at most health food stores. But niacin supplementation can cause facial flushing. An extended release from of niacin has gained widespread clinical use. Clinical trials are now investigating a novel “flush-free” form of the vitamin.
Fibrates, another class of drug already on the market that potentially can raise HDL levels, are usually used in tandem with statins to treat high cholesterol. But they can cause potentially serious side effects, including kidney damage.
A few years ago, researchers showed that infusions of a synthetic form of HDL, called “ApoA1 Milano,” could significantly reduce atherosclerotic lesions as detected by intravascular ultrasound. But the need to inject it by vein every week makes this option impractical for widespread use.
For several years, Fazio and Linton have studied a protein that binds fatty acids in both macrophages and fat cells. As such, the adipocyte fatty acid binding protein (aP2) plays a crucial role in inflammation and insulin resistance, factors driving both diabetes and atherosclerosis.
“It turns out that in addition to cholesterol, fatty acids play critical roles in promoting both plaque build-up in the arteries and the development of adult onset diabetes,” Linton explains. “Coronary heart disease is the most common cause of death in diabetes,” he says, “and we believe that aP2 is a critical link between these disease processes.”
In a recent article published in the journal Nature, the Vanderbilt researchers and their colleagues at the Harvard School of Public Health and Bristol-Myers Squibb reported that an aP2 inhibitor prevented the development of atherosclerosis and diabetes in mice.
“These studies are tremendously exciting,” says Linton, “because they support the potential development of a single therapeutic approach for the treatment of diabetes and the prevention of coronary heart disease.”