Gloria Lena Vega

In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia.

The causes of primary moderate hypercholesterolemia are not understood, but some patients have reduced fractional clearance rates (FCRs) for low density lipoproteins (LDL). This could be due to either decreased activity of LDL receptors or to a defect in structure (or composition) of LDL that reduces its affinity for receptors. To distinguish between these causes, simultaneous turnover rates of autologous and normal homologous LDL were determined in 15 patients with primary moderate hypercholesterolemia. In 10, turnover rates of both types of LDL were indistinguishable, which indicated that autologous LDL was cleared as efficiently as normal homologous LDL. In five others, FCRs for autologous LDL were significantly lower than for homologous LDL. Two of the latter five were treated with mevinolin, and although FCRs for both types of LDL rose during treatment, differences in FCRs between the two types of LDL persisted. In these five patients, autologous LDL appeared to be a poor ligand for LDL receptors.

Kinetic heterogeneity of low density lipoproteins in primary hypertriglyceridemia.

The kinetics of two subfractions of low density lipoproteins (LDL) were examined in nine patients with primary hypertriglyceridemia. LDL was subjected to equilibrium ultracentrifugation, and three patterns of LDL subfractions were noted. The LDL of five patients with moderate hypertriglyceridemia (plasma triglycerides (TG) ranging from 333 to 580 mg/dl) appeared to contain two distinct subfractions. One was less dense and had a high TG content; the other was more dense and had a reduced content of all lipids, particularly cholesterol. Each subfraction was labeled separately and was reinjected into the patient. Of the two subfractions, the more dense LDL usually had a higher fractional catabolic rate (FCR), although the turnover rates of both subfractions for these hypertriglyceridemic patients were higher than normal. Two other patients with mild hypertriglyceridemia had only a single LDL after gradient equilibrium ultracentrifugation. This fraction was divided into less dense and more dense subfractions, and their FCR was determined. In both patients, turnover rates of the two subfractions were similar and both were In the normal range. Finally, two more patients with mildly elevated TG had a very dense LDL, besides having a single, less dense band. For both patients, the FCR for the less dense and very dense subfractions were similar, although the denser LDL had a greater fraction in the extravascular compartment. Thus, patients with primary moderate hypertriglyceridemia often have distinct subfractions that have different turnover rates. For patients with mild hypertrlglyceridemia, the LDL is more homogenous, and Its subfractions are kinetically similar.

Effect of Intensive Diabetes Treatment on Low-Density Lipoprotein Apolipoprotein B Kinetics in Type I Diabetes

The metabolism of low-density lipoprotein (LDL) was studied in six insulin-dependent (type I) diabetic patients during a 7-wk period of conventional and intensive therapy with insulin. Plasma glucose and HbA1c were normalized, demonstrating the effectiveness of our intensive treatment program. Plasma lipoprotein profiles and LDL apolipoprotein B kinetic parameters were estimated during conventional and then during intensive therapy for each patient. Intensive therapy resulted in a significant reduction of plasma and LDL cholesterol and an increase in high-density lipoprotein (HDL) cholesterol. The lower LDL levels resulted from a decreased production of lipoprotein rather than an increased fractional catabolic rate. These results are consistent with our previous observations of very-low-density lipoprotein (VLDL) metabolism during intensive therapy. VLDL production is significantly reduced; thus, a decreased production of LDL supports the contention that intensive therapy with insulin in normolipemic type I diabetic patients reduces the production of lipoproteins containing apolipoprotein B rather than increasing the clearance, and therapy also increases HDL cholesterol. Both of these effects may be beneficial in reducing the risk for coronary heart disease in type I diabetes.

Mechanisms of primary hypercholesterolemia in humans

Approximately 15% of middle-aged Americans have primary hypercholesterolemia, that is, plasma cholesterol levels in excess of 250 mg/dl. The risk for coronary heart disease in these patients is at least twice that of patients with a baseline level of 200 mg/dl. Only 2% of hypercholesterolemic patients have familial hypercholesterolemia. The causes of elevated cholesterol concentrations in the remaining patients have not been determined. Three major mechanisms may be responsible: overproduction of lipoproteins by the liver, reduced activity of receptors for low-density lipoproteins (LDL), and low affinity of circulating LDL for receptors. We have examined each of these mechanisms for primary hypercholesterolemia by isotope kinetic techniques. All three types have been identified, and the underlying causes of each are under investigation.

Low-density lipoprotein metabolism in cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is a rare disorder characterized by a defect in conversion of cholesterol into bile acids, increased plasma levels of cholestanol, and accumulations of sterols in tendons, brain, and coronary arteries. Despite the presence of tendon xanthomas, patients with CTX frequently have low levels of plasma cholesterol and low density lipoproteins (LDL). The mechanisms for a low LDL are not understood. The present study, therefore, was carried out to examine the metabolism of LDL in a 58-year-old black man with CTX. This particular patient had an LDL-cholesterol in the mid-normal range (149 +/- 6 mg/dL). Nonetheless, his fractional catabolic rate (FCR) for LDL-apolipoprotein (apo-LDL) was 0.45 pools/d, which was increased compared to 15 aged-matched men (FCR, 0.30 +/- 0.01 pools/d). His production rate for apo-LDL (18.5 mg/kg-d) also was increased compared to those of middle-aged men (13.5 +/- 2.5 mg/kg-d). Since the underlying defect in CTX can be reversed by administration of chenodeoxycholic acid (chenodiol), the patient was treated with chenodiol (250 mg 4X daily), and measurements of LDL kinetics were repeated. During chenodiol therapy, his LDL-cholesterol concentration rose significantly to 165 +/- 12 mg/dL; his FCR for apo-LDL fell to 0.29 pools/d; and his production rate of apo-LDL declined to 14.4 mg/kg-d. We postulate that chenodiol suppressed the excessive synthesis of cholesterol and bile acids, which had two effects. It curtailed both the overproduction of LDL and the excessive synthesis of LDL receptors, the latter being responsible for the high FCR of apo-LDL in the untreated state.