New Suspect, Apo B, May Factor In Genetic Cause Of High Cholesterol

"Familial combined hyperlipidemia (FCHL) affects an estimated one in 10 Americans with premature heart disease, making it a leading contributor to death and disability in our society" says Jonathan Q. Purnell, M.D., the study’s lead author and assistant professor in the division of endocrinology at Oregon Health Sciences University in Portland.

Although FCHL has been under study for nearly 30 years, many aspects of it remain a mystery. The trail is hot, he says, but the clues have been muddied by complicating factors.

FCHL results from defects in the metabolism of lipoproteins, or blood fats, that lead to high total cholesterol, high triglycerides or both. People with FCHL also have a preponderance of small, dense low-density lipoprotein (LDL) particles, which are more likely to accumulate in the arteries and cause atherosclerosis than the more buoyant LDL found in people without FCHL, Purnell explains. In the general population, about one in 100 Americans are affected.

People with FCHL tend to be insulin resistant, their bodies fail to use insulin efficiently to usher glucose into the cells for energy. Insulin resistance without FCHL is itself associated with high triglycerides and accumulation of small, dense LDL particles, so many investigations have centered on insulin resistance as the primary suspect in FCHL’s cholesterol abnormalities.

However, another metabolic abnormality may help explain the link with heart disease. People with FCHL overproduce a substance called apolipoprotein B (apoB), a structural component of cholesterol containing particles made by the liver whose importance in FCHL has remained unclear.

To characterize the relationship between insulin resistance and increased apo B, Purnell’s group used two control groups rather than the usual one. The first group was matched by age to 11 FCHL subjects. The second by age and weight. The investigators then measured total cholesterol, triglycerides, apoB, abdominal fat, and insulin resistance in all three groups.

The study, conducted at the University of Washington at Seattle, found that FCHL subjects had significantly higher levels of total cholesterol, triglycerides, very-low density lipoproteins (VLDL), LDL and apo B compared with both control groups. Except for a lower HDL cholesterol level in the age- and weight-matched control group compared with the other control group, lipid levels were similar between these groups.

In addition, researchers found that for any level of insulin resistance or amount of deep abdominal fat, the FCHL subjects’ apoB levels were higher than controls. Deep abdominal fat was an important determinant for insulin resistance, but did not fully account for the elevated blood fat levels – indicating the existence of yet to be discovered genes (or gene) in FCHL that control production of apoB by the liver which, in turn, determines the high blood levels of cholesterol and triglyceride.

"Now, for the average person with FCHL, we can think of the condition as the result of two separate processes that occur together – the increased abdominal fat and insulin resistance, which are common traits in our society, and the mysterious turning on of the liver to over secrete blood fats," he says. "It appears that the risk for heart disease in FCHL extends beyond insulin resistance and the amount of deep abdominal fat and also likely extends beyond the presence of small, dense LDL particles, which occurs in both FCHL and insulin resistance.

So now, the investigation is shifting to finding the gene or genes responsible for the increases in apoB, the researchers say. That, in turn, could lead to new treatments aimed at reducing the heart disease risk.

"The search is on for these other culprits," says Purnell. "But that doesn’t minimize the importance of insulin resistance and the intra-abdominal fat, though. Those are still important components and may be targets for therapy."

In the meantime, weight loss, a low-fat diet and regular exercise to reduce deep abdominal fat, as well as cholesterol-lowering drugs if necessary, are very important for people with FCHL, he says.

The work raises important questions for physicians in how they assess cardiovascular risk, writes Robert Eckel, M.D., in an accompanying editorial. Eckel is a professor of medicine at the University of Colorado Health Sciences Center and chairperson of the American Heart Association’s Council on Nutrition, Physical Activity and Metabolism.

"Once LDL cholesterol levels are below goal, whether or not further reductions of apoB are associated with reductions in cardiovascular risk remains untested. Nevertheless, at present, this may be the best avenue to pursue."

Co-authors include: Steven E. Kahn, M.D., and Robert S. Schwartz, M.D., and senior author John D. Brunzell, M.D.

The study was funded in part by the National Institutes of Health.