The effects of dietary fats on plasma cholesterol, serum lipoproteins, and apoproteins (Apo), A-1, B, and CIII were studied. Twelve men consumed three different cholesterol-free formula diets in which polyunsaturated and saturated fats were partially substituted (20% of calories) for monoenoic fats with a constant of 40% of calories from fat. Total cholesterol and low-density lipoprotein cholesterol dropped from base-line values of 166 and 103 to 133 and 81 mg/dl (sat), 127 and 71 mg/dl (mono), and 123 and 65 mg/dl (poly), respectively. High-density lipoprotein cholesterol changed very little from base-line values of 46 to 40 mg/dl (sat), 45 mg/dl (poly), and 43 mg/dl (mono). The plasma concentrations of ApoB declined from base-line values of 80.3 mg/dl to 54.6 mg (mono), 51.8 mg (poly), and 59.6 mg (sat) while Apo CIII and Apo AI did not show any changes. This study demonstrates that: 1) changes in dietary fat affect serum lipids, lipoproteins, and apoproteins even when consumed on a cholesterol-free diet, and 2) omega-6 polyunsaturated fat lowers low-density lipoprotein cholesterol, total cholesterol, and ApoB to a greater extent than monounsaturated or saturated fat, 3) consumption of a cholesterol-free formula diet results in significant decreases in the concentrations of total and low-density lipoprotein cholesterol in plasma when compared to values obtained on a mixed food home diet containing approximately 300 mg cholesterol/day.

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Despite an absence of low density lipoproteins (LDLs) and-chylomicron remnants from plasma, the rates of cholesterol synthesis or the number of LDL receptors expressed on freshly isolated cells from patients with abetalipoproteinemia are not markedly increased. These observations suggest that other lipoprotein particles present in the plasma of patients with abetalipoproteinemia may regulate LDL receptor activity and the rates of cellular cholesterol synthesis in this disorder. In the present report we have studied the effects of lipoprotein fractions from the plasma of normal subjects, patients with abetalipoproteinemia, and a patient with dysbetalipoproteinemia on the binding, internalization, and degradation of "SI-labeled LDL ('25I-LDL) by cultured human fibroblasts. LDL from normal subjects or the high density lipoprotein fraction HDL2 from the plasma of patients with abetalipoproteinemia effectively down-regulated LDL receptor activity (>50% inhibition at 20 jug of protein per ml). HDL2 from the plasma of patients with abetalipoproteinemia also effectively reduced the binding, internalization, and degradation of '25I-LDL by cultured human fibroblasts. 125I-HDL2 from the plasma of patients with abetalipoproteinemia was bound, internalized, and degraded by cultured human fibroblasts; this process was competitively inhibited by unlabeled normal LDL or HDL2 from abetalipoproteinemic plasma and was 1/6th to 1/8th times as high when 12I-HDL2 was incubated with fibroblasts from a patient with receptor-negative homozygous familial hypercholesterolemia. We conclude that lipoproteins present in the HDL2 fraction of plasma from patients with abetalipoproteinemia (which are relatively rich in apoprotein E) are effective regulators of LDL receptor activity in normal human fibroblasts. These in vitro findings may explain why the in vivo rates of cholesterol synthesis and the number of LDL receptors expressed on freshly isolated cells from patients with abetalipoproteinemia are not markedly increased.The importance of specific high-affinity receptors that facilitate the cellular uptake of plasma lipoproteins in the regulation of cholesterol homeostasis has been well documented (1,2). Two distinct receptors have been identified on hepatic cell membranes (3, 4). One of these, the low density lipoprotein (LDL or BE) receptor specifically recognizes lipoprotein particles that contain either apoprotein B (LDL) or certain apoprotein Erich high density lipoprotein particles (such as the HDLC particles, which can be induced in dog plasma by diets rich in cholesterol) (5). This LDL or B,E receptor is expressed in many tissues, including the liver and adrenal cortex, and appears to be identical to the specific high-affinity LDL receptors originally identified on cultured human fibroblasts (6), which are defective in patients with familial hypercholesterolemia .(7). A second receptor (the apoprotein E receptor) that recognizes only lipoproteins containing apoprotein E (e.g., HDLc and chylomicron remnants) has been shown t...

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Freshly isolated mononuclear leukocytes have been reported to-show changes in cholesterol synthesis and high-affinity degradation of low-density lipoproteins (LDL) that parallel those that occur in the liver. To examine whether hypolipidemic therapy in patients with heterozygous familial hypercholesterolemia influences cholesterol homeostasis in their mononuclear cells we assessed the effects of colestipol and nicotinic acid (alone and in combination) on the rates of high-affinity "SI-labeled LDL degradation and on the rates of cholesterol and phosphatidylcholine biosynthesis by freshly isolated cells. Rates of '25I-labeled LDL degradation were lower in mononuclear cells from patients with heterozygous familial hypercholesterolemia on no medication (3.1 ng per 4 X 106 cells per 5 hr) than in cells from normal control subjects (6.1 ng per 4 X 106 cells per 5 hr) and, in the former patients, the values were not significantly affected by therapy with nicotinic acid. In contrast, freshly isolated mononuclear cells from patients receiving colestipol degraded "2I-labeled LDL at nearnormal rates (5.0 ng per 4 x 106 cells per 5 hr). The rates of cholesterol synthesis were also higher in mononuclear cells isolated from patients treated with colestipol than in cells from untreated patients or from those receiving nicotinic acid; in contrast the rate of synthesis of phosphatidylcholine did not show any consistent changes. Similar results were obtained in a smaller number of patients studied longitudinally, in which colestipol therapy significantly increased rates of cholesterol synthesis and high-affinity degradation of '25I-labeled LDL by freshly isolated mononuclear cells. We conclude that previously observed changes in cholesterol homeostasis in the liver of patients treated with bile acid sequestrants are paralleled by similar changes in freshly isolated mononuclear cells and that these cells offer an accessible model for further studies on how diet and pharmacologic agents influence cellular cholesterol homeostasis in humans.Optimal treatment of patients with heterozygous familial hypercholesterolemia (FH) necessitates the use of diet and hypolipidemic medication, among which the bile acid-binding resins (colestipol and cholestyramine) and nicotinic acid are the most efficacious (1,2). Recent studies have clarified the mechanisms by which colestipol and cholestyramine decrease plasma concentrations of low-density lipoproteins (LDL) in both experimental animals and in humans (3, 4). Both drugs bind bile acids in the intestinal lumen, thereby interrupting the enterohepatic circulation and stimulating an increase in the hepatic conversion of cholesterol to bile acids. This in turn depletes the hepatic pool of cholesterol and results in two compensatory changes; an increase in the de novo biosynthesis of cholesterol (5) has been shown in humans and an increase in the number of specific high-affimity LDL receptors on hepatocyte membranes has been shown in rabbits and dogs (4, 6). The latter change also promotes an...