Serum Cholesterol Is Correlated With the Incidence of Atherosclerosis & Coronary Heart Disease
Atherosclerosis is an inflammatory disease characterized by the deposition of cholesterol and cholesteryl ester from the plasma lipoproteins into the artery wall and is a major cause of heart disease. Elevated plasma cholesterol levels (>5.2 mmol/L) are one of the most important factors in promoting atherosclerosis, but it is now recognized that elevated blood triacylglycerol is also an independent risk factor. Diseases in which there is a prolonged elevation of levels of VLDL, IDL, chylomicron remnants, or LDL in the blood (eg, diabetes mellitus, lipid nephrosis, hypothyroidism, and other conditions of hyperlipidemia) are often accompanied by premature or more severe atherosclerosis. There is also an inverse relationship between HDL (HDL2) concentrations and coronary heart disease, making the LDL:HDL cholesterol ratio a good predictive parameter. This is consistent with the function of HDL in reverse cholesterol transport. Susceptibility to atherosclerosis varies widely among species, and humans are one of the few in which the disease can be induced by diets high in cholesterol.
Diet Can Play an Important Role in Reducing Serum Cholesterol
Hereditary factors play the most important role in determining the serum cholesterol concentrations of individuals; however, dietary and environmental factors also play a part, and the most beneficial of these is the substitution in the diet of polyunsaturated and monounsaturated fatty acids for saturated fatty acids. Plant oils such as corn oil and sunflower seed oil contain a high proportion of ω6 polyunsaturated fatty acids, while olive oil contains a high concentration of monounsaturated fatty acids. ω3 fatty acids found in fish oils are also beneficial (see Chapter 21). On the other hand, butter fat, beef fat, and palm oil contain a high proportion of saturated fatty acids. Sucrose and fructose have a greater effect in raising blood lipids, particularly triacylglycerols, than do other carbohydrates.
One of the mechanisms by which unsaturated fatty acids lower blood cholesterol levels is by the upregulation of LDL receptors on the cell surface by poly- and monounsaturated as compared with saturated fatty acids, causing an increase in the catabolic rate of LDL, the main atherogenic lipoprotein. ω3 fatty acids are believed to be protective because of their anti-inflammatory and triacylglycerol lowering effects. In addition, saturated fatty acids cause the formation of smaller VLDL particles that contain relatively more cholesterol, and they are utilized by extrahepatic tissues at a slower rate than are larger particles—tendencies that may be regarded as atherogenic.
Lifestyle Affects the Serum Cholesterol Level
Additional factors considered to play a part in coronary heart disease include high blood pressure, smoking, male gender, obesity (particularly abdominal obesity), lack of exercise, and drinking soft as opposed to hard water. Factors associated with elevation of plasma FFA followed by increased output of triacylglycerol and cholesterol into the circulation in VLDL include emotional stress and coffee drinking. Premenopausal women appear to be protected against many of these deleterious factors, and this is thought to be related to the beneficial effects of estrogen. There is an association between moderate alcohol consumption and a lower incidence of coronary heart disease. This may be due to elevation of HDL concentrations resulting from increased synthesis of apo A-I and changes in activity of cholesteryl ester transfer protein. It has been claimed that red wine is particularly beneficial, perhaps because of its content of antioxidants. Regular exercise lowers plasma LDL but raises HDL. Triacylglycerol concentrations are also reduced, due most likely to increased insulin sensitivity, which enhances the expression of lipoprotein lipase.
When Diet Changes Fail, Hypolipidemic Drugs Can Reduce Serum Cholesterol & Triacylglycerol
A family of drugs known as statins have proved highly efficacious in lowering plasma cholesterol and preventing heart disease. Statins act by inhibiting HMG-CoA reductase and up-regulating LDL receptor activity. Examples currently in use include atorvastatin, simvastatin, fluvastatin, and pravastatin. Ezetimibe reduces blood cholesterol levels by inhibiting the absorption of cholesterol by the intestine by blocking uptake via the Niemann-Pick C-like 1 protein. Other drugs used include fibrates such as clofibrate, gemfibrozil, and nicotinic acid, which act mainly to lower plasma triacylglycerols by decreasing the secretion of triacylglycerol and cholesterol-containing VLDL by the liver. Since PCSK9 reduces the number of LDL receptors exposed on the cell membrane it has the effect of raising blood cholesterol levels, thus drugs that inhibit its activity are potentially antiatherogenic and several such compounds are currently in clinical trials.
Primary Disorders of the Plasma Lipoproteins (Dyslipoproteinemias) Are Inherited
Inherited defects in lipoprotein metabolism lead to the primary condition of either hypo- or hyperlipoproteinemia (Table 26–1). For example, familial hypercholesterolemia (FH), causes severe hypercholesterolemia and is also associated with premature atherosclerosis. The defect is most often in the gene for the LDL receptor, so that LDL is not cleared from the blood. In addition, diseases such as diabetes mellitus, hypothyroidism, kidney disease (nephrotic syndrome), and atherosclerosis are associated with secondary abnormal lipoprotein patterns that are very similar to one or another of the primary inherited conditions. Virtually all of the primary conditions are due to a defect at a stage in lipoprotein formation, transport, or degradation (see Figures 25–4, 26–5, and 26–6). Not all of the abnormalities are harmful.
TABLE 26–1Primary Disorders of Plasma Lipoproteins (Dyslipoproteinemias) ||Download (.pdf) TABLE 26–1 Primary Disorders of Plasma Lipoproteins (Dyslipoproteinemias)
|Name ||Defect ||Remarks |
|No chylomicrons, VLDL, or LDL are formed because of defect in the loading of apo B with lipid. ||Rare; blood acylglycerols low; intestine and liver accumulate acylglycerols. Intestinal malabsorption. Early death avoidable by administration of large doses of fat-soluble vitamins, particularly vitamin E. |
Familial alpha-lipoprotein deficiency
|All have low or near absence of HDL. ||Tendency toward hypertriacylglycerolemia as a result of absence of apo C-ll, causing inactive LPL. Low LDL levels. Atherosclerosis in the elderly. |
Familial lipoprotein lipase deficiency (type I)
|Hypertriacylglycerolemia due to deficiency of LPL, abnormal LPL, or apo C-ll deficiency causing inactive LPL. ||Slow clearance of chylomicrons and VLDL. Low levels of LDL and HDL. No increased risk of coronary disease. |
|Familial hypercholesterolemia (type IIa) ||Defective LDL receptors or mutation in ligand region of apo B-100. ||Elevated LDL levels and hypercholesterolemia, resulting in atherosclerosis and coronary disease. |
|Familial type III hyperlipoproteinemia (broad beta disease, remnant removal disease, familial dysbetalipoproteinemia ||Deficiency in remnant clearance by the liver is due to abnormality in apo E. Patients lack isoforms E3 and E4 and have only E2, which does not react with the E receptor.a ||Increase in chylomicron and VLDL remnants of density <1.019 (β-VLDL). Causes hypercholesterolemia, xanthomas, and atherosclerosis. |
|Familial hypertriacylglycerolemia (type IV) ||Overproduction of VLDL often associated with glucose intolerance and hyperinsulinemia. ||Cholesterol levels rise with the VLDL concentration. LDL and HDL tend to be subnormal. This type of pattern is commonly associated with coronary heart disease, type II diabetes mellitus, obesity, alcoholism, and administration of progestational hormones. |
|Familial hyperalphalipoproteinemia ||Increased concentrations of HDL. ||A rare condition apparently beneficial to health and longevity. |
|Hepatic lipase deficiency ||Deficiency of the enzyme leads to accumulation of large triacylglycerolrich HDL and VLDL remnants. ||Patients have xanthomas and coronary heart disease. |
|Familial lecithin:cholesterol acyltransferase (LCAT) deficiency ||Absence of LCAT leads to block in reverse cholesterol transport. HDL remains as nascent disks incapable of taking up and esterifying cholesterol. ||Plasma concentrations of cholesteryl esters and lysolecithin are low. Present is an abnormal LDL fraction, lipoprotein X, found also in patients with cholestasis. VLDL is abnormal (β-VLDL). |
|Familial lipoprotein(a) excess ||Lp(a) consists of 1 mol of LDL attached to 1 mol of apo(a). Apo(a) shows structural homologies to plasminogen. ||Premature coronary heart disease due to atherosclerosis, plus thrombosis due to inhibition of fibrinolysis. |