High serum levels of cholesterol usually are due to too high levels of LDL cholesterol. This condition, called hypercholesterolemia, increases the risk for coronary heart disease. A high LDL is dangerous in both men and women. Some forms of high LDL are inherited, but most appear to result from excessive intakes of saturated fats and cholesterol. Besides the well known genetic deficiency of LDL receptors, which was discovered by Drs. Joseph Goldstein and Michael Brown, Dr. Vega and co-workers have discovered three other causes of high LDL. First, she found that some patients have abnormal LDL particles that cannot be removed from circulation because the abnormal LDL does not recognize the receptors. The defect resides in the protein of LDL, called apolipoprotein B-100. This disorder is called familial defective apolipoprotein B-100. The molecular defect underlying familial defective apolipoprotein B-100 was discovered in collaborative studies with investigators at the Gladstone Foundation, University of California, San Francisco. The defect is a substitution of glutamine for arginine at position 3500 of the apo B molecule (see description of molecular interaction of apo B-100 with LDL receptor by Innerarity). Since the initial observations, many patients have been diagnosed with this disease, particularly in Germany. It is also noteworthy, that patients originally classified as having receptor defects also were found to have familial defective apolipoprotein B-100.
Second, Dr. Vega showed that a high LDL can be due to LDL that is overloaded with cholesterol. In this form of hypercholesterolemia, every LDL particle carries an excess amount of cholesterol. This type of hypercholesterolemia is particularly common in women, but about 20% of men with elevated LDL cholesterol also have it.
Third, Dr. Vega has discovered that a high LDL level can result from an excess formation of LDL due to failure of the liver to remove VLDL, the precursor of LDL. The latter finding has prompted her to look more carefully at the metabolism of the precursors of LDL. As is well known, LDL is a breakdown product of lipoproteins called very low density (VLDL). VLDL are enriched in triglyceride, hence they are also called triglyceride-rich lipoproteins (TGRLP). The metabolism of TGRLP appears to be one factor regulating serum concentrations of LDL cholesterol.
