Forms Of Hyperlipidemia Research Articles

Cholesterol level in peripheral blood lymphocytes: Relationship with ischemic heart disease in patients with various forms of hyperlipidemia

Even though a correlation between the incidence of ischemic heart disease(IHD) and the plasma level of "atherogenic" cholesterol has been demostrated in a number of extensive population studies [1-3], the mechanism underlying this phenomenon remains unclear. It is generally accepted that a rise of plasma cholesterol (Ch) level above 6.5 mmol/ l i ter increases the risk of atherosclerotic plaque formation [4]. Cholesterol accumulation in the vascular intima is due to the transformation of macrophages and smooth muscle cells into foam cells [5,6], which does not reflect the Ch content of other cells in the body. Cholesterol accumulat ion in tissues may occur without pronounced hypercholesterolemia. Yu. M. Lopukhin has described "cholesterosis" of red blood cells in patients with hypercholesterolemia [7]. However, these non-nucleated cells do not have their system for own controlling Ch balance, and the Ch concentration in their plasma membrane simply reflects the intensity of the concentration gradient transport. The mechanism responsible for the coupling

Transgenic mice expressing full-length human apolipoprotein B-100. Full-length human apolipoprotein B mRNA is essentially not edited in mouse intestine or liver.

Apolipoprotein (apo) B-100 mRNA is edited in the small intestine (in all mammals examined) and the liver (in mice and rats only) to produce apoB-48 mRNA. ApoB mRNA editing involves a C-->U conversion of the first base of the codon CAA for Gln-2153 in apoB-100, changing it to an in-frame stop codon (UAA). The edited mRNA encodes apoB-48, which is colinear with the N-terminal 48% of apoB-100. ApoB mRNA editing can be reproduced in vitro using cellular extracts from one species to edit synthetic apoB mRNA sequences from a different species. Editing of transcripts from transfected genes also appears not to be species-specific. We have produced transgenic mice that express full-length human apoB-100 mRNA at high levels in the liver and small intestine. Human apoB-100 (a 550-kDa protein) but not apoB-48 (a 260-kDa protein) is detected in total plasma (at approximately 22 mg/dl) and in very low density and low density lipoproteins. The endogenous mouse plasma apoB concentration is reduced by approximately 45% in the transgenic animals. Thus, the transgenic mice form an animal model for familial hyperapolipoprotein B, an inherited form of hyperlipidemia. To our surprise, we found that the full-length human apoB mRNA consists of > 99% apoB-100 mRNA in both the liver and small intestine; < 1% of edited (apoB-48) mRNA was detected. The proportions of endogenous mouse apoB-48 (edited) mRNA (60 and 90% in the liver and small intestine, respectively) were identical in transgenic mice and their nontransgenic littermates. Therefore, full-length human apoB mRNA is resistant to editing by the mouse editing enzyme in vivo; the unchanged proportion of endogenous mouse apoB-48 mRNA in the transgenic mice suggests that the human mRNA competes poorly with the mouse sequence for interacting with the editing enzyme. This observation has implications for the sequence specificity and mechanism of RNA editing. Furthermore, we should exercise caution in the interpretation of in vitro RNA-editing experiments.

Marine Oil Capsule Therapy for the Treatment of Hyperlipidemia

Because marine oil capsules may vary widely in their content of omega-3 fatty acids, saturated fat, and cholesterol composition and, therefore, their biologic potency, we compared the lipid-lowering effects of three representative preparations in patients with different forms of hyperlipidemia. The ester and triglyceride forms of marine oil both effectively lowered triglyceride, but the response of low-density lipoprotein cholesterol was variable; it declined modestly in patients with hypercholesterolemia and was either unchanged or increased in those with hypertriglyceridemia. The saturated fat and cholesterol content of the marine oil preparation appeared to influence the low-density lipoprotein cholesterol response. Therefore, marine oil capsules are useful for lowering levels of very-low-density lipoprotein cholesterol, but the large dose required to achieve and sustain this effect (4.5 g of omega-3 fatty acids, or nine to 18 capsules daily) may limit long-term compliance.

Current Strategies for Atherosclerosis and Lowering Cholesterol

Atherosclerosis is a multifactorial disorder in which nutritional factors are closely related to a number of the manifestations of the disease. Sounder nutritional principles might therefore prevent atherosclerosis itself or its major complications. Optimising nutrients would diminish monocyte adhesion to endothelium, suppress platelet aggregation, prevent oxidative modification of lipoproteins, minimise activation of coagulant factors and reduce the flux of cholesterol and of atherogenic lipoproteins through plasma. Optimising the mix of dietary fatty acids should have the highest priority. Emphasis should be placed on those fatty acids, such as those derived from fish, which modify several cardiovascular risk factors, including plasma lipids, blood pressure and coagulation factors. Reduction of risk factors is also achieved but to a lesser extent by reducing total fat intake, reducing dietary cholesterol, optimising the mix of starches and fibre and increasing plant foods generally. A developing strategy is to identify genetic predisposition to environmentally induced hyperlipidaemia, since most forms of hyperlipidaemia reflect interactions between genetic and dietary factors.

Normal and pathological lipoprotein metabolism.

Lipids are transported in plasma as lipoproteins, and an increase in 1 or more classes of lipoprotein underlies all forms of hyperlipidaemia. Physiological influences on lipoprotein metabolism are age, gender, bodyweight, diet and exercise. Pathological influences include genetic abnormalities, endocrine dysfunction, renal impairment and iatrogenic effects. Three inherited forms of hyperlipidaemia which predispose to atherosclerosis are familial hypercholesterolaemia (FH), type III hyperlipoproteinaemia and familial combined hyperlipidaemia (FCH), each of which has its own distinctive metabolism defect. In FH, deficiency of low density lipoprotein (LDL) receptors results in the accumulation in plasma of LDL-cholesterol because of a reduction in the receptor-mediated component of LDL catabolism. In type III hyperlipoproteinaemia, the presence of an abnormal apo E isoform (apo E2) in remnant particles leads to their accumulation in plasma, through nonrecognition by remnant receptors and a consequent reduced rate of hepatic uptake. In contrast, there is no primary catabolic defect in FCH, in which increased levels of very low density lipoprotein (VLDL) and LDL are largely the result of increased synthesis.

Population and individual strategies for the prevention of coronary heart disease. Policy of the European Atherosclerosis Society.

Coronary heart disease (CHD) risk factors affect a large proportion of European adult populations; hence most CHD results from the exposure of many people to moderately elevated risk factor levels. The population strategy is directed to improving the health-related behaviour of the entire population, by means of mass education and administrative measures aimed at nutrition, smoking and exercise; these measures are reviewed in some detail. This approach is inadequate for minimising risk in the minority in whom pronounced risk factor levels are present (e.g. major forms of hyperlipidaemia); such persons require individual therapy in a clinical setting, i.e. an individual strategy. The European Atherosclerosis Society (EAS) endorses both strategies and regards them as complementary. It advocates a case-finding approach to identifying those people requiring individual care. Although lipid risk factors, like blood pressure, are continuous variables, the EAS has defined action limits for plasma cholesterol, triglyceride and HDL-cholesterol concentrations; the interpretation of these is influenced by the presence and extent of other risk factors and of cardiovascular disease, and by age and sex. Recently the EAS has produced guidelines on the recognition and treatment of hyperlipidaemia. These provide sufficient step by step detail to permit the effective, safe management of most hyperlipidaemic patients by the non-specialised physician, with advice on dietary and drug therapies, and the investigation and management of all major forms of hyperlipidaemia. The main features of these guidelines are described in this paper.

Dietary therapy for different forms of hyperlipoproteinemia.

Diet is the first line of therapy for hypercholesterolemia. The major dietary factors raising the plasma cholesterol are saturated fatty acids, cholesterol, and excess total calories. For almost all forms of hyperlipidemia, the first principle of dietary therapy is to reduce saturated fatty acids, decrease cholesterol, and curtail excess calories. In patients with severe hypercholesterolemia, marked restrictions of diet may be necessary. For these patients, drugs may be required to control cholesterol levels. However, the majority of patients with elevated plasma cholesterol can achieve a satisfactory reduction of cholesterol levels by diet, and drugs will not be necessary. Dietary therapy alone is adequate for most patients with familial forms of hypertriglyceridemia, but for a few patients drugs are required.

Polymorphism of apolipoprotein E

Apolipoprotein E from human serum shows a genetic polymorphism determined by two autosomal codominant alleles, Apo En and Apo Ed. Homozygosity for the gene Apo Ed (phenotype Apo E-D) results in primary dysbetalipoproteinemia, but only some individuals with this phenotype develop gross hyperlipidemia (hyperlipoproteinemia type III). Vertical transmission of dysbetalipoproteinemia represents pseudodominance due to the high frequency of the gene Apo Ed. Dysbetalipoproteinemia is already expressed in childhood. To assess the influence of other genes on the expression of hyperlipidemia in phenotype Apo E-D, comparative studies were carried out in kindreds of hypercholesterolemic (group A) and normo- or hypocholesterolemic probands with dysbetalipoproteinemia (group B). This demonstrated the occurrence of familial (non-type III) forms of hyperlipidemia in group A but not in group B kindreds. Distribution of lipoprotein phenotypes in five of the group A kindreds was consistent with the occurrence of familial combined hyperlipidemia. Apo E phenotypes and hyperlipidemia segregated independently. It is concluded that primary dysbetalipoproteinemia is a frequent monogenic variant of lipoprotein metabolism, but not a disease. Coincidence in one individual of genes for this specific dyslipoproteinemia with any of the genes for monogenic or polygenic forms of familial hyperlipidemia results in hyperlipoproteinemia type III. Hence hyperlipoproteinemia type III is caused by at least two non-allelic genes and is a polygenic disorder.

Plasma, apolipoprotein A‐I and A‐II levels in hyperlipidemia

Some of the component moieties of high density lipoproteins (HDL) were analyzed in normal subjects and in patients with hyperlipidemia. Apoproteins A-I and A-II were quantified by radioimmunoassay, HDL cholesterol and triglycerides were assessed on heparin-MnCl2 supernates of fasting plasmas. We found that HDL is enriched in triglycerides in all forms of hyperlipidemia, while the proportion of ApoA-II is unaltered and the proportion of ApoA-I is decreased. Thus, the composition of HDL is altered in hupertirglyceridemia. The molecular associations of ApoA-I and ApoA-II in plasma were also examined by assaying the apoprotein contents of plasma fractions prepared by ultracentrifugation and by gel filtration column chromatograpy. The ApoA-I contents of d smaller than 1.063 fraction increased in hyperlipidemia from smaller than 0.5% to approximately 2%, but the ApoA-I contents of the d greater than 1.21 fraction remained at less than 12% of total plasmas with triglyceride levels smaller than 1500 mg/dl. d greater than 1.21 ApoA-I rose to 23% in one plasma with a triglyceride level of greater than 1700 mg/dl. On column chromatography, ApoA-I eluted with the lipoproteins and also in a fraction whose molecular weight (MW) appeared to be approximately 50,000 daltons. The proportion of plasma ApoA-I which eluted in the 50,000 MW peak was positively correlated with plasma triglyceride levels, but at triglyceride levels of less than 1500 mg/dl, less than 20% of ApoA-I was in the 50,000 MW peak. Between levels of approximately 2000 and 12,000 mg/dl, the percentage "50,000 M.W. ApoA-1" was 20-25%. The ApoA-II contents of d smaller than 1.063 fractions were also increased in hyperlipidemia, but greater than 95% of ApoA-II was found in the HDL fractions in both normal and hyperlipidemic plasma both by column chromatography and ultracentrifugation. Thus, the molecular association of ApoA-I appears to be altered in hyperlipidemia.

Hyperlipidemia, Atherosclerosis, and Diabetes

At present the two different mechanisms underlying the hypertriglyceridemia of diabetes are reasonably well defined. The rationale of therapy has grown from this knowledge. One form of hyperlipidemia is due to the hyperinsulinemia which results from the patient's resistance to insulin. The approach to treatment aims to overcome the insulin resistance. In most patients this is done by treating their obesity. The other form of hypertriglyceridemia results from insulin deficiency and is treated by bringing the patient's diabetes under control. There is strongly suggestive evidence that hypertriglyceridemia may be associated with a high risk of atherosclerosis. The reason for treating hypertriglyceridemia in general, and in the diabetic in particular, is to reduce this risk. However, it must be conceded that, at the moment, there is no information about the effect of lower triglyceride levels on the incidence of atherosclerosis. Hence much epidemiologic research is needed before our rationale for treatment can move from the realm of hope to the realm of definite proof. In the mean time an attack on this and the other risk factors is the best way we have to attempt to prevent the major complication of diabetes, atherosclerosis.

Results of treatment of hyperlipidemias; short term effect on cholesterol metabolism.

There has been a recent tendency to reduce the different forms of hyperlipidemia to fewer categories and to attempt a more unified approach to the dietary management of the hyperlipidemias(l). There is some justification for this approach, but the H.G.H.McMaster Lipid Research Clinic still uses the internationally accepted World Health Organization classification(2) based on Fredrickson et al. This is because we believe that this classification of hyperlipoproteinemia(HLP) with, all its imperfections has etiological, genetic, epidemiological, diagnostic and therapeutic potential. It should be remembered that in all 5 types of hyperlipoproteinemia that plasma cholesterol levels may be elevated, although this is most commonly seen in types IIa and b, III and IV HLP. The majority of this discussion will be devoted to the one parameter namely plasma lipids, which are routinely measured in the Lipid Clinic. No attempt will be made to elaborate on other important cholesterol pools--the liver, the intestine and its contents, adipose tissue and other tissue stores.

Diet and atherosclerosis.

Diet and atherosclerosis are closely linked, both aetiologically and therapeutically. The aetiological association can be demonstrated most satisfactorily in animal experiments. In human beings the evidence must necessarily be more indirect and is largely based on dietary trials and epidemiological surveys linking the intake of cholesterol and saturated fat with morbidity and mortality from coronary disease. A modifying influence which has gained increasing recognition over recent years is the individual response to a given diet. This variability appears to be largely genetically determined, certainly in the defined primary hyperlipidaemic states, and possibly within the normal ranges of serum cholesterol levels. A change in food habits should be fully utilized therapeutically in any form of hyperlipidaemia, whether as a primary preventive measure before clinical diseases of atherosclerotic origin become manifest or in secondary prevention to delay further morbidity and mortality. With good dietary adherence, lipid levels may return to normal and there may be additional favourable effects on intravascular thrombosis. Many problems remain to be solved on the public health issue of advising changes in the national diet. A number of countries in which an atherogenic diet is habitually eaten have decided in favour of such a recommendation. Public education, identification of persons at risk and provision of readily available skilled medical and dietary counselling should constitute a national health project with rewarding long-term results.

Mechanisms of action of clofibrate on cholesterol metabolism in patients with hyperlipidemia

The influence of clofibrate on cholesterol metabolism in patients with hyperlipidemia was studied by means of sterol balance and isotope kinetic techniques and by measurements of flow rates of cholesterol through the biliary tract. Long-term balance studies were carried out on a metabolic ward in 24 patients with all currently recognized types of hyperlipidemia; in five other patients with hypercholesterolemia, pool sizes and turnover rates of cholesterol were defined by compartmental analysis before and after three years' daily administration of the drug. Except in fat-induced hypertriglyceridemia (two patients), clofibrate caused reduced plasma levels of triglycerides and cholesterol in all categories of hyperlipidemia. As a general rule, excretion of cholesterol into bile and feces was significantly increased and fecal bile acid excretion was decreased, regardless of the type of lipoprotein abnormality. Despite a net increase in steroid excretion in most patients with hyperlipidemia, cholesterol synthesis was not increased; indeed, in many patients synthesis appeared to be decreased. While the data obtained in 29 patients were not always consistent, the bulk of the evidence suggests that, in all forms of hyperlipidemia except fat-induced hyperglyceridemia, the drug causes an increased output of cholesterol while simultaneously inhibiting any compensatory increase in cholesterol synthesis. Therefore, it appeared that the increased excretion of steroids was most likely derived from cholesterol stored in tissues. This conclusion was strengthened by finding that long-term administration of the drug can cause marked reduction in body pools of cholesterol. These findings are reflected clinically by resolution of skin and tendon xanthomatosis. However, it is not yet known whether the accumulation of cholesterol in arterial walls that is part of the process of atherogenesis can be inhibited or reversed by the drug.

Clofibrate in biliary cirrhosis

Clofibrate (Atromid S - ICI) is the drug most widely used in this country for reducing abnormally high plasma lipids, and for treating xanthomatosis.1 It is not effective in all forms of hyperlipidaemia, but until now it has not been known to raise lipid levels. A recent report, however, describes four patients with primary biliary cirrhosis and hypercholesterolaemia in whom clofibrate raised the serum cholesterol. In three of the patients the skin xanthomas became more severe. When clofibrate was discontinued the cholesterol level fell again. The explanation for this surprising effect so far remains obscure. Clofibrate did not affect bilirubin, alkaline phosphatase and transaminase levels.2 We conclude that the drug should not be used in patients with biliary cirrhosis.