Abnormalities In Lipoprotein Metabolism Research Articles

Dietary Fatty Acids, Lipoproteins, and Cardiovascular Disease

Dietary fat quality and quantity significantly affect the metabolism of all the plasma lipoproteins and probably constitute the most significant dietary determinants of plasma lipoprotein levels. Since the major role of the plasma lipoproteins is the transport of exogenous and endogenous fat, this would be expected of a highly regulated, metabolically homeostatic system. The data clearly show that dietary fat saturation affects all aspects of lipoprotein metabolism, from synthesis to intravascular remodeling and exchanges to receptor-mediated and nonspecific catabolism. The experimental data regarding dietary fatty acid effects on lipoprotein metabolism are complicated and at times contradictory due to the large degree of metabolic heterogeneity in the population, which, when coupled with the known abnormalities of lipoprotein metabolism associated with certain types of hyperlipoproteinemia, can present responses from A to Z. It is clear that the same dietary pattern has different effects in different individuals and that complicating factors of individuality raise some concerns regarding generalized dietary recommendations. As new knowledge of the role of dietary factors and CVD risk develops, and our abilities to characterize the individual patient's response to dietary interventions become more refined, it may be possible to specify dietary fat intervention from a patient-oriented concept rather than a single all-purpose diet approach. Thus it would be possible to design dietary interventions to match patient needs and gain both efficacy and compliance. With the spectrum of approaches possible--low fat, moderate fat with MUFA, n-3 PUFA, etc.--we should be able to approach dietary interventions to reduce CVD risk at both a population-based level and a patient-specific level. There remains much to learn regarding the effects of dietary fatty acids on the synthesis, intravascular modifications, and eventual catabolism of the plasma lipoproteins. The area of lipoprotein metabolism in health and disease, of its modifications by diets and drugs, and of the contributions of genetic heterogeneity to these processes is one of notable advances over the past two decades and continues to be an area of intense investigation.

Cholesterol and Atherosclerosis: Diagnosis and Treatment

This single-authored, colorfully illustrated book provides an excellent written and visual presentation of the complex biochemical and physiological pathways of lipoprotein metabolism. The book meets the primary goal of the author—to show how abnormalities in lipoprotein metabolism relate to the development of various dyslipidemias and clinical atherosclerosis. The first of four major units covers cholesterol, atherosclerosis, and coronary heart disease, including cholesterol and lipoprotein metabolism and transport, the steps in atherogenesis, and the evidence supporting the cholesterol— coronary disease relationship. The unit on classification of lipid disorders is more clinically oriented and provides a useful outline of causes of genetic and acquired hypercholesterolemia. The approach to dietary therapy for hyperlipidemia is rational, buttressed by graphic presentation of appropriate mechanistic metabolic pathways. Finally, indications and practical recommendations for drug therapy for hyperlipidemia are given. Information is accumulating rapidly about cholesterol and fatty acid transport; the origin and role of very low—density

Lipoprotein Physiology in Nondiabetic and Diabetic States: Relationship to Atherogenesis

Abnormalities of plasma lipid and lipoprotein concentrations are common in both insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus. In general, individuals with IDDM who are untreated or inadequately treated have elevations in both postprandial and fasting triglyceride levels in association with reduced activity of lipoprotein lipase. Low-density lipoprotein (LDL) cholesterol levels can rise when insulin deficiency impacts on LDL-receptor function. When patients with IDDM are treated and plasma glucose levels well controlled, plasma very-low-density lipoprotein (VLDL) triglyceride and LDL cholesterol levels are usually normal. In addition, plasma high-density lipoprotein (HDL) cholesterol levels are normal or elevated in well-controlled IDDM subjects. In NIDDM, increased VLDL triglyceride and reduced HDL cholesterol concentrations are common and are only partially related to glycemic control. Overproduction of VLDL leads to hypertriglyceridemia, which can be exacerbated if lipoprotein lipase activity is also reduced. The regulation of LDL levels is complex; catabolism can be reduced if significant insulin deficiency exists or increased if significant hypertriglyceridemia is present. The reduced levels of HDL cholesterol in NIDDM appear to be related to increased exchange of HDL cholesteryl esters for VLDL triglycerides, although other mechanisms may exist. The roles of insulin resistance, obesity, and independently inherited abnormalities of lipoprotein metabolism in the etiology of dyslipidemia of NIDDM are complex and require further investigation. Finally, the effects of diabetes on glycosylation of apoproteins; on other lipid enzymes, particularly hepatic triglyceride lipase; on lipoprotein surface lipids; and on hepatic uptake of remnants have only just begun to be defined. In view of the marked increase in atherosclerotic cardiovascular disease in individuals with diabetes mellitus, prompt attention to and aggressive therapy for dyslipidemia should be a central component of care for these patients.

Impaired binding of low density lipoprotein to hepatic membranes from uremic guinea pigs.

Chronic renal failure is associated with abnormalities in lipoprotein metabolism that may contribute to premature atherosclerosis and early mortality in patients on dialysis. In previous studies, we found that plasma clearance of radiolabelled low density lipoprotein (LDL) was retarded in nephrectomized guinea pigs left with one-sixth of normal functioning renal mass. To elucidate potential mechanisms of delayed LDL clearance, we compared binding of LDL to hepatic membranes from both normal and uremic guinea pigs. One hundred micrograms of the 8000-100,000 X g hepatic microsomal protein was incubated with 125I-labelled normal guinea pig LDL (10-150 micrograms/mL) for 1 h at 37 degrees C, and the membrane washed and pelleted by centrifugation in a Beckman Ti 42.2 rotor. Parallel incubations with excess unlabelled LDL were done to determine specific binding. LDL specific binding to uremic hepatic membranes was significantly impaired compared with normal ones. The major abnormality, as determined by Scatchard transformation of the binding data, was a reduction of the apparent maximal binding of LDL to uremic membranes, with an average Bmax of 4.1 micrograms/mg protein compared with 6.6 micrograms/mg protein for normal hepatic microsomes. The affinity of LDL for uremic liver membranes was only slightly diminished with a mean apparent Kd of 35.2 micrograms/mL in comparison with 21.8 micrograms/mL for normal liver membranes. These results provide a biochemical explanation for the diminished LDL clearance in uremia and may account for the dyslipidemia of renal failure.

Epidemiologic and clinical aspects of insulin resistance and hyperinsulinemia

Epidemiologic studies have shown that insulin is a risk factor for coronary heart disease (CHD). Clinical studies have also demonstrated positive correlations between insulin and blood pressure, triglycerides, total cholesterol, fibrinogen, and plasminogen activator inhibitor. Moreover, there is an inverse correlation between insulin and high-density lipoprotein (HDL). These studies have provided evidence in support of the biologic plausibility of epidemiologic observations, but they have not clearly established insulin's role in the pathogenesis of human cardiovascular diseases (CVD) such as hypertension. In fact, there is considerable evidence that insulin resistance (abnormal nonoxidative glucose disposal), not hyperinsulinemia, is the primary insulin-related abnormality in human hypertension, and that hyperinsulinemia occurs as a response to insulin resistance. Skeletal muscle appears to be the primary site of insulin resistance in essential hypertension, although other organs, such as the kidneys and liver—key sites for cell and water homeostasis and lipoprotein regulation, respectively—may respond normally to insulin. Adipocytes also appear to be a site of insulin resistance. Thus, the putative interrelationship between hyperinsulinemia and insulin resistance, on the one hand, and with blood pressure and lipoproteins, on the other, is a complex one and may involve organ-specific insulin resistance. Altered cation transport is one of several mechanisms by which insulin resistance might raise blood pressure. The Na +,K +-ATPase and Ca 2+-ATPase pumps are insulin sensitive. Thus, when insulin resistance is present, the activity of these pumps in the smooth muscle of the arterial wall might be reduced. This would lead to an intracellular accumulation of sodium and calcium, thereby sensitizing the vascular wall to pressor substances. Moreover, secondary hyperinsulinemia will occur, and insulin has been shown to stimulate sympathetic nervous system activity and to increase renal tubular absorption of sodium. Insulin is also a growth factor and therefore might have a trophic effect on the vessel wall, one that could initiate and/or sustain hypertension as well as atherosclerosis. Abnormal lipoprotein metabolism is yet another possible explanation for the accelerated atherosclerosis that has been observed in persons with abnormal carbohydrate tolerance and insulin resistance. Hyperinsulinemia and insulin resistance both play a role in the expression of elevated very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels as well as in the depression of HDL levels. Coronary risk reduction has been disappointing when blood pressure has been lowered with treatment regimens based on thiazide diuretics and/or β blockers. Thiazides and some β blockers may further impair tissue insulin sensitivity and often cause blood lipoprotein abnormalities. These drug-induced derangements in insulin and lipoprotein metabolism might offset a portion of the expected coronary risk reduction when blood pressure is lowered with these drugs. Thus, new strategies employing pharmacologic therapy that does not engender further insulin resistance and lipoprotein metabolic abnormalities appear to be critical in maximizing coronary risk reduction in persons with hypertension.

Insulin resistance and compensatory hyperinsulinemia: Role in hypertension, dyslipidemia, and coronary heart disease

Resistance to insulin-stimulated glucose uptake and hyperinsulinemia may play a central role in the cause and clinical course of patients with non-insulin-dependent diabetes mellitus, high blood pressure, abnormalities of lipoprotein metabolism, and coronary heart disease. This article summarizes the evidence in support of this general hypothesis.

Abnormalities of Lipoprotein Metabolism in the Nephrotic Syndrome

Abnormalities of Lipoprotein Metabolism in the Nephrotic Syndrome

Receptor Function of Low-Density Lipoproteins in Werner’s Syndrome

Abnormal lipoprotein metabolism and its cause were studied in 10 patients with Werner's syndrome. Seven of the 10 patients had hypercholesterolemia (greater than 250 mg dl-1). A significant positive correlation (p less than 0.01) was found between serum total cholesterol levels and LDL receptor activity. In monocyte-derived macrophages of patients with this syndrome, the uptake, lysosomal hydrolysis and re-esterification of free cholesterol are enhanced. This abnormal accumulation of cholesterol ester may cause accelerated conversion of macrophages to foam cells in Werner's syndrome.

Acylation-stimulatory activity in hyperapobetalipoproteinemic fibroblasts: enhanced cholesterol esterification with another serum basic protein, BP II.

Cultured fibroblasts from patients with familial hyperapobetalipoproteinemia (hyperapoB) were used to determine if a defect in lipid metabolism was present. Three basic proteins (BP I, BP II, and BP III) were isolated from normal human serum by preparative isoelectric focusing, preparative SDS/PAGE, and reversed-phase HPLC. The Mr and pI values of these proteins were 14,000 and 9.10 for BP I, 27,500 and 8.48 for BP II, and 55,000 and 8.73 for BP III. These proteins differed significantly in their content of arginine, cysteine, proline, histidine, serine, and methionine. BP I appears to be the same protein as acylation-stimulating protein, but BP II and BP III appeared different from acylation-stimulating protein and other lipid carrier proteins. BP I, BP II, and BP III stimulated the incorporation of [14C]oleate into lipid esters in normal fibroblasts, an effect that was time and concentration dependent. In hyperapoB cells, BP II markedly increased (up to 9-fold) the incorporation of [14C]oleate into cholesteryl ester compared with that in normal cells; in addition, there was a 50% decrease in the stimulation of triglyceride acylation and cholesterol esterification with BP I. No difference between normal and hyperapoB cells was observed with BP III. In summary, the identification of another serum basic protein, BP II, led to the elucidation of another cellular defect in hyperapoB fibroblasts, enhanced cholesterol esterification, which may be related to the precocious atherosclerosis and abnormal lipoprotein metabolism seen in hyperapoB.

Lipoprotein abnormalities in the progression of renal disease

Chronic renal disease is a progressive process. Implicated factors include abnormalities of the clotting cascade, altered prostaglandin metabolism, increased dietary protein intake, and abnormalities of lipoprotein metabolism. Several animal models have associated increased serum concentrations of cholesterol and triglycerides with progressive decline in renal function. The mechanism(s) of lipid-associated renal injury are unknown but may relate to lipid uptake by glomerular mesangial cells, hyperviscosity secondary to the hyperlipidemia, and a direct effect of the lipids on the glomerular basement membrane. Patients with chronic renal disease have well recognized increases in serum lipid concentrations. Whether lowering these concentrations will delay or prevent progressive renal failure or renal histologic abnormalities is unknown, but studies are underway to evaluate the effect of lipid-lowering agents in patients at risk for chronic progressive renal disease.

Abnormalities of Lipoprotein Metabolism in Patients with the Nephrotic Syndrome

Patients with the nephrotic syndrome characteristically have multiple abnormalities of lipoprotein metabolism, but the cause and exact nature of these abnormalities are uncertain. In this study, we measured serum lipids and apoproteins in 57 patients with the nephrotic syndrome. We also determined the kinetic indexes of low-density lipoprotein (LDL) metabolism in six patients, and again in three of the six after recovery. The patients with the nephrotic syndrome had elevated serum concentrations of cholesterol, triglycerides, and phospholipids, which were confined to the lipoproteins containing apoprotein B. The serum concentrations of high-density lipoproteins and the associated A-I and A-II apoproteins were similar in the patients with the nephrotic syndrome and normal subjects. The relative proportions of lipids and their positive association with the increased serum concentrations of apoproteins B, C-II, C-III, and E suggest quantitative rather than qualitative differences in the lipoproteins. All the patients had lipiduria, which probably reflected the excretion of high-density lipoproteins, although no intact immunoreactive apoprotein A-I was found in urine. Serum albumin concentrations were inversely related to serum lipid concentrations in the patients, the severity of the hypoalbuminemia corresponding to the degree of change in serum lipoprotein concentrations. The kinetic studies of lipoprotein metabolism revealed an overproduction of LDL apoprotein B that returned to normal after recovery. The elevated serum concentrations of LDL cholesterol, other lipids, and apoprotein B in patients with uncomplicated nephrotic syndrome are due to reversible increases in lipoprotein production.

Activity of platelet-activating factor (PAF) acetylhydrolase in plasma from healthy habitual cigarette smokers

The activity of platelet-activating factor acetylhydrolase, a specific metabolizing enzyme of platelet-activating factor (PAF), in plasma of 39 male subjects was determined radiochemically by the method of Stafforini et al., (1987) J Biol Chem 262: 4223-4230, to clarify to what extent PAF affects atherosclerotic disorders induced by habitual smoking. The subjects examined included 18 habitual smokers (mean age: 62 +/- 10.6 years) and 21 age-matched nonsmokers. Plasma PAF acetylhydrolase activity was higher in the smokers than in the nonsmokers. There was no difference between smokers and nonsmokers in platelet aggregability in response to PAF or ADP. A higher apoprotein B/apoprotein A-I ratio in smokers as compared to nonsmokers was the only manifestation of abnormal lipoprotein metabolism in the former group. In the smokers, plasma PAF acetylhydrolase activity was directly proportional to total cholesterol, LDL-cholesterol, triglyceride, apoprotein B, LDL-cholesterol/HDL-cholesterol or apoprotein B/apoprotein A-I, and inversely proportional to HDL-cholesterol or apoprotein A-I. The results obtained suggest that alterations in PAF acetylhydrolase levels result from a slightly abnormal lipoprotein metabolism. Determination of plasma PAF acetylhydrolase activity is useful to study the role of PAF in atherosclerotic changes induced by smoking.

Inheritable abnormal lipoprotein metabolism in Werner's syndrome similar to familial hypercholesterolaemia

Studies were made on the abnormality of lipoprotein metabolism and its cause in 10 patients with Werner's syndrome. Seven of the 10 patients had hypercholesterolaemia (above 250 mg dl-1). Six of the seven patients with hypercholesterolaemia had thickened Achilles' tendons (greater than 9 mm). A significant positive correlation (P less than 0.01) was found between the serum total cholesterol levels and the thickness of Achilles' tendons in these 10 patients, suggesting that the substance precipitated in the thickened tendons is derived from serum cholesterol. Some first-degree relatives of three patients with both hypercholesterolaemia and xanthoma-like thickening of Achilles' tendons also suffered from hypercholesterolaemia. Moreover, the low density lipoprotein (LDL) receptor activities in peripheral lymphocytes of five patients with both hypercholesterolaemia and xanthoma-like tendons were significantly (P less than 0.001) lower than those of controls, whereas the LDL receptor activities of two patients without hypercholesterolaemia were almost the same as those of controls. These findings suggest that, at least these five patients with lower lymphocyte LDL receptor activities, and probably another patient with both hypercholesterolaemia and xanthoma-like thickening of Achilles' tendons suffered from familial hypercholesterolaemia (FH). If this is the case, this high frequency of association of Werner's syndrome with FH (in six of 10 patients) suggests some relationship between these two diseases.

FREQUENT PRESENCE OF REMNANT LIKE PARTICLES IN DIABETES MELLITUS

Remnant-like particles (RLP) were studied in 139 diabetic patients. RLP were those lipoproteins that did not bind to an immunoaffinity gel mixture using anti-apo B-100 and apo A-1 monoclonal antibodies, and were shown to provide a useful index for atherogenic chylomicron and very low density lipoprotein remnants. RLP-positive findings (RLP≥ 5 mg/dl) in diabetics (42%) were significantly higher in prevalence than those in controls (12%) (p<0.001). RLP-positive findings were more frequently observed in diabetics with lower levels of serum total cholesterol (T-ch) and serum triglyceride (TG) than in controls. In general, the higher the T-ch or TG level, the more frequent RLP-positive results were observed both in diabetics and in controls. In particular, all controls were RLP positive when their TG level was greater than 300mg/dl, as were all diabetics whose level was more than 200mg/dl. No relationship was detected between RLP and serum fasting plasma glucose, Hb-A1c, method of intervention or complications of diabetes mellitus. The determination of RLP could be a useful index to evaluate abnormal lipoprotein metabolism in diabetes mellitus.

High-density lipoprotein cholesterol is reduced in patients with sarcoidosis.

Sarcoidosis is a disease in which the proliferation of monocyte-macrophage-derived cells is observed. In other diseases characterized by expansion of the monocyte-macrophage system, such as Gaucher's disease and myeloid metaplasia, abnormalities of lipoprotein metabolism have been demonstrated. To determine whether similar abnormalities in lipoprotein cholesterol concentrations could be identified in patients with sarcoidosis, we studied total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol as well as triglyceride levels in 52 patients with biopsy-proven sarcoidosis. Patients had no other medical disorders and were not being treated with corticosteroids or antimalarial agents. Blood samples were collected by venipuncture after an overnight fast. Plasma total cholesterol and triglyceride levels were measured using enzymatic techniques. Lipoprotein cholesterol was quantified by lipoprotein fractionation. HDL cholesterol was measured as cholesterol remaining in the supernatant after precipitation of LDL and very-low-density lipoprotein from whole plasma by the heparin-maganese chloride method. Computation was used to determine the level of LDL cholesterol. We found significantly reduced levels of total cholesterol (183.9 +/- 27.6 versus 194.3 +/- 16.5 mg/dl, mean +/- SD, p = 0.021) and HDL cholesterol (41.2 +/- 13.0 versus 51.9 +/- 6.1 mg/dl, p = 0.0001) in sarcoid patients versus an age-, sex-, and race-matched reference group. Differences were not observed in triglyceride or LDL cholesterol levels (p greater than 0.05). These findings are similar to those observed in the myeloproliferative diseases, Gaucher's disease, and rheumatoid arthritis and suggest a functional role for monocytes-macrophages in the regulation of serum lipoprotein cholesterol levels.

Multiple risk factor evaluation in a hypertension clinic.

Hypertension is associated with abnormal lipoprotein metabolism, which may be exacerbated by some groups of antihypertensive drugs and represents an additional powerful coronary heart disease risk factor. Of our Hypertension Clinic population, 75% had a total fasting serum cholesterol greater than 5.2 mmol/l. Dietary advice and adjustment of antihypertensive therapy has achieved significant reductions in total cholesterol, serum triglycerides and body weight (14%, 18% and 4.3%, respectively) in a cohort of 65 patients reassessed over a period of 3-21 months. The reduction in cholesterol is likely to represent at least a 28% reduction in the risk of a major coronary heart disease event, even before taking account of any improvement in other coronary heart disease risk factors.

Abnormal Lipoprotein Metabolism in Normolipidemic Diabetics with Special Reference to Relationships between Insulin

Abnormal Lipoprotein Metabolism in Normolipidemic Diabetics with Special Reference to Relationships between Insulin

Activity of platelet-activating factor (PAF) acetylhydrolase in plasma from patients with ischemic cerebrovascular disease

Platelet-activating factor (PAF) is metabolized by a specific enzyme, PAF acetylhydrolase, which may play an important role in the manifestation of the biological activities of PAF in vivo. The activity of PAF acetylhydrolase in plasma of patients with ischemic stroke was higher than that in healthy controls. The incidence of irreversible platelet aggregation in response to PAF, as well as to ADP, was found to be higher in patients than in controls. The patients whose platelets responded with irreversible aggregation to PAF displayed a higher activity of plasma PAF acetylhydrolase than those with only reversible aggregation. In controls, PAF acetylhydrolase activity correlated positively, although weakly, with LDL-cholesterol, which may reflect the major role of LDL in carrying this enzyme. However, since there was no significant difference in plasma levels of lipids and apoproteins between patients and controls (except for apo B) and there was no significant relationship between the enzyme activity and the levels of other lipids and apoproteins, it is unlikely that increased plasma level of PAF acetylhydrolase activity in stroke patients is accounted for by an abnormality of lipoprotein metabolism. Platelet hyperfunction may be associated with augmented generation of PAF, which, in turn, may bring about the induction of the inactivating enzyme, PAF acetylhydrolase.

Abnormalities in lipoprotein metabolism in Gaucher type 1 disease

We have previously described an association between Gaucher type 1 disease and reduced levels of total, low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol. Plasma concentrations of apolipoprotein B and apolipoprotein AI were reduced in these subjects, while plasma apolipoprotein E (apoE), which can be synthesized and secreted by macrophages, was increased. To study the pathophysiologic basis for these changes in lipoprotein and apolipoprotein levels, we studied very low density lipoprotein (VLDL), LDL, and HDL metabolism in-depth in four subjects with Gaucher disease. Gel filtration of their plasma revealed that apoE was present in essentially a single population of lipoproteins in the large HLD range. In subject no. 4, studied presplenectomy and post-splenectomy, plasma apoE levels fell after surgery in association with a redistribution of apoE among the plasma lipoproteins to a pattern seen in normal subjects. Determination of the rates of secretion and catabolism of VLDL apoB and triglyceride were within normal limits. The reduced plasma levels of LDL and HDL cholesterol, and of both plasma apoB and apoAI, were associated with increased fractional catabolic rates of these apolipoproteins in LDL and HDL. These results indicate that the hypocholesterolemia present in subjects with Gaucher type 1 disease is associated with increased fractional catabolism of LDL and HDL. These findings, together with the evidence for alternations in plasma apoE metabolism in this disorder, suggest a role for the macrophage as the basis for these abnormalities.

9 Hormones and lipoprotein metabolism

The influence of hormones on lipoprotein metabolism is of major clinical interest for three main reasons. First, abnormalities of hormone secretion and/or actions (e.g. insulin) may participate in the pathophysiology of lipoprotein aberrations and possibly the atherogenic risk accompanying common medical disorders such as endogenous hypertriglyceridaemia, obesity, and diabetes mellitus. Second, hormones are important regulators of fuel and substrate partitioning, in response to the physiological adaptations of fasting and feeding (e. g. insulin and glucagon), growth and development (e.g. growth hormone and thyroxin), pregnancy and lactation (e.g. gonadal steroids and prolactin), and physical or mental stress (e.g. catecholamines and glucocorticoids) and their prolonged overor undersecretion could induce persistent abnormalities in lipoprotein metabolism. Third, hormonal preparations and their derivatives (e.g. gonadal steroids, glucocorticoids and adrenergic antagonists) are prescribed for the management of a wide variety of medical conditions, and their long-term use might be attended by deleterious changes in lipoprotein metabolism.