Human Biochemistry, Volume 1 - Murray R. 1993

Bioenergetics and Metabolism of Carbohydrates and Lipids
Synthesis, Transport, and Excretion of Cholesterol
Cholesterol Elimination and Bile Acid Salt Formation - Clinical Aspects

Hypercholesterolemia can be treated by interrupting the enterohepatic Circulation of Bile acids. Evidence indicates that this approach achieves a significant reduction in plasma Cholesterol levels. Enterohepatic circulation can be interrupted either pharmacologically with cholestyramine resin (Questran) or surgically via ileal bypass. In both cases, bile acid reabsorption is blocked. As a result, the normal feedback inhibition exerted by bile acids is lifted, prompting a much larger fraction of hepatic cholesterol to be converted into bile acids to maintain a constant bile acid pool size. Regulatory mechanisms respond by increasing the number of hepatic LDL receptors, which in turn enhances LDL uptake and lowers plasma cholesterol concentrations.

Cholesterol, Atherosclerosis, and CORONARY Heart DISEASE

Numerous researchers have observed a correlation between elevated serum lipid levels and the incidence of coronary heart disease and atherosclerosis in humans. Serum cholesterol is widely considered the primary lipid factor contributing to these conditions; however, a correlation between the risk of developing these disorders and the concentration of triacylglycerols has also been noted. Patients suffering from arterial atherosclerosis may exhibit the following abnormalities: 1) elevated VLDL concentration with normal LDL concentration; 2) elevated LDL concentration with normal VLDL concentration; or 3) elevated concentrations of both lipoprotein fractions. Furthermore, an inverse relationship exists between HDL concentration (HDL₂) and the likelihood of coronary heart disease, leading to the hypothesis that The ratio of cholesterol content in the LDL and HDL fractions is the most informative clinical indicator. This aligns with the well-established roles of LDL as a cholesterol transporter to Tissues and HDL as a reverse cholesterol transporter from tissues.

Atherosclerosis involves the deposition of cholesterol and its esters—delivered via apo-B-100-containing Lipoproteins—within the Connective Tissue of arterial walls. Premature or severe atherosclerosis is frequently observed in diseases characterized by chronically elevated Blood levels of VLDL, IDL, or LDL (such as Diabetes Mellitus, lipoid nephrosis, hypothyroidism, and other hyperlipidemic states).

Animal experiments designed to induce atherosclerosis have demonstrated that various species exhibit differing degrees of susceptibility. For instance, atherosclerosis can be triggered in rabbits, pigs, monkeys, and humans by feeding them high-cholesterol diets, whereas rats, dogs, and cats are naturally resistant. Nevertheless, atherosclerosis can be induced in dogs and rats following thyroidectomy or the administration of thiouracil. Notably, a low blood cholesterol level is a hallmark of hyperthyroidism.

Individual blood cholesterol concentrations are heavily influenced by hereditary factors.

Substantial attention has been focused on replacing dietary saturated Fatty acids with polyunsaturated fatty acids as a means of lowering blood cholesterol levels. Vegetable oils rich in linoleic acid—such as peanut, cottonseed, corn, and soybean oils—help reduce plasma cholesterol, whereas the consumption of butter, beef tallow, and coconut oil, which are predominantly saturated, leads to an increase. Sucrose and fructose are more potent than other CARBOHYDRATES in elevating blood lipid levels, primarily triacylglycerols.

The exact mechanism by which polyunsaturated fatty acids lower cholesterol remains unclear. Several hypotheses have been proposed: one suggests The stimulation of cholesterol excretion into the intestine, while another posits the activation of cholesterol oxidation into bile acids. It is also possible that the METABOLISM of cholesterol esters formed with polyunsaturated fatty acids proceeds more rapidly in The Liver and other tissues, thereby accelerating their turnover and elimination. Alternatively, some researchers believe that the action of polyunsaturated fatty acids is largely mediated by an increased rate of LDL Catabolism, which shifts the distribution of cholesterol between plasma and tissues in favor of the latter. Saturated fatty acids promote The formation of VLDL particles containing relatively high amounts of cholesterol, which are cleared by extrahepatic tissues more slowly than larger particles.

The Development of coronary heart disease is also promoted by Hypertension, smoking, obesity, physical inactivity, and the consumption of soft Water instead of hard water. Elevated plasma free fatty acid levels lead to enhanced hepatic secretion of VLDL and, consequently, a greater influx of triacylglycerols and cholesterol into the bloodstream. Factors that trigger surges or fluctuations in free fatty acid levels include emotional stress, nicotine from smoking, caffeine consumption, and large, infrequent meals. Many of these risk factors appear to have little discernible effect on premenopausal women, likely because their blood HDL levels are higher than those of men and postmenopausal women.

Hypolipidemic Drugs

When serum lipid levels cannot be controlled through dietary modification alone, hypolipidemic pharmacological agents may be employed. Several drugs are known to block Cholesterol Biosynthesis at various Stages of the metabolic pathway. While many hypolipidemic agents produce adverse side effects, the fungal-derived HMG-CoA reductase inhibitors, compactin and mevinolin, effectively lower plasma LDL cholesterol with virtually no undesirable side effects. The hypocholesterolemic agent sitosterol blocks intestinal cholesterol absorption. Ion-exchange resins such as colestipol and cholestyramine (Questran) bind bile salts, prevent their reabsorption, and thereby promote their fecal excretion. Neomycin similarly inhibits bile salt reabsorption. The hypolipidemic efficacy of clofibrate and gemfibrozil is attributable, at least in part, to shifting the flux of hepatic free fatty acids away from Esterification and toward oxidation, which reduces the secretion of triacylglycerol- and cholesterol-rich VLDL by liver Cells. Additionally, these drugs accelerate the lipoprotein lipase-catalyzed Hydrolysis of VLDL triacylglycerols. Probucol appears to enhance receptor-independent LDL catabolism. Nicotinic acid reduces the flux of FFAs by inhibiting lipolysis in adipose tissue, thereby suppressing hepatic VLDL production.

Disorders of Plasma Lipoprotein Metabolism (Dyslipoproteinemias)

A small proportion of the population exhibits inherited lipoprotein metabolism disorders that lead to primary hyper- or hypolipoproteinemia. Patients suffering from diabetes mellitus, hypothyroidism, and atherosclerosis display lipoprotein abnormalities that closely resemble those seen in hereditary dyslipoproteinemias. Virtually all inherited forms of these diseases stem from defects in one of the stages of lipoprotein synthesis, transport, or degradation (see Figs. 26.4, 26.5, and 27.6). It should be noted, however, that not all hereditary lipoprotein disorders pose a serious health hazard to the patient.

A. Hypolipoproteinemias

1. Abetalipoproteinemia. This rare inherited disorder is characterized by the absence of ß-lipoproteins (LDL) in Blood Plasma. Patients with abetalipoproteinemia exhibit very low plasma lipid levels, with acylglycerols being virtually undetectable due to impaired chylomicron and VLDL formation. Acylglycerols accumulate within the intestine and liver. The underlying molecular defect involves impaired synthesis of apolipoprotein B.

2. Familial hypobetalipoproteinemia. In this condition, LDL concentrations range from 10% to 50% of those found in healthy individuals, yet the body retains The ability to form chylomirons. Comparing this state with abetalipoproteinemia suggests that apo-B plays a crucial role in triacylglycerol transport. Most individuals with hypobetalipoproteinemia are asymptomatic and live a normal lifespan.

3. Familial alpha-lipoprotein deficiency (Tangier disease). Homozygous patients exhibit a near-total absence of plasma HDL, accompanied by massive accumulation of cholesterol esters in various tissues. Chylomicron formation and hepatic VLDL secretion remain unimpaired. However, lipoprotein Electrophoresis reveals a complete absence of pre-ß-lipoproteins, while the ß-lipoprotein band is broader than normal and contains endogenous triacylglycerols. The pre-ß region contains alternative apolipoproteins that normally originate from HDL. Affected patients lack apolipoprotein C-II, an essential activator of lipoprotein lipase, which accounts for the characteristic hypertriacylglycerolemia observed in this condition.

B. Hyperlipoproteinemias

1. Familial lipoprotein lipase deficiency (Type I). This condition is characterized by extremely delayed clearance of chylomicrons from the circulation, leading to their marked accumulation in the blood. VLDL levels may be elevated, whereas LDL and HDL levels are depressed. The condition is exacerbated by fat-rich diets. Treatment relies on a low-fat, high-complex-carbohydrate diet. One variant of this disorder is associated with a deficiency of apolipoprotein C-II, the essential cofactor for lipoprotein lipase.

2. Familial hypercholesterolemia (Type II). Patients with this disorder present with elevated levels of ß-lipoproteins (LDL) driven by an increase in total plasma cholesterol. In Type IIb hypercholesterolemia, VLDL levels may also be elevated, which can slightly raise total triacylglycerol levels; nonetheless, unlike other hyperlipoproteinemias, the serum remains clear. Lipid deposition in peripheral tissues (e.g., xanthomas, atheromas) is common. Type II hypercholesterolemia can also manifest secondary to hypothyroidism. The disease is apparently linked to a reduced rate of intravascular LDL clearance resulting from defective LDL receptor-mediated uptake, thereby significantly increasing the risk of atherosclerosis. Treatment involves a diet low in cholesterol and saturated fats. Wolman disease (characterized by the pathological accumulation of cholesterol esters) also presents with hypercholesterolemia, driven by deficient activity of lysosomal cholesterol ester hydrolase in Cell types such as fibroblasts, which normally process LDL.

3. Familial hyperlipoproteinemia, Type III ("broad ß-band disease", remnant clearance defect, familial dysbetalipoproteinemia). This condition is characterized by an accumulation of VLDL remnants with a density of less than 1.019. On electrophoretograms, they appear as a broad ß-band (ß-VLDL). The disorder is accompanied by hypercholesterolemia and hypertriacylglycerolemia, along with xanthomas and atherosclerotic lesions in both peripheral and coronary Arteries. Treatment centers on weight-loss dietary therapy, recommending a regimen rich in complex carbohydrates and unsaturated fats with very low cholesterol content. The molecular basis involves impaired hepatic metabolism of remnant lipoproteins due to a structural defect in apolipoprotein E (which normally exists as three common isoforms: E₂, E₃, and E₄). Patients with Type III hyperlipoproteinemia express only apolipoprotein E₂, which is incapable of binding properly to apo-E receptors.

4. Familial hypertriacylglycerolemia (Type IV). This condition features elevated levels of endogenously produced triacylglycerols (VLDL), accompanied by a parallel increase in cholesterol concentration. The disease is frequently accompanied by impaired glucose tolerance, while LDL and HDL levels are subnormal. Type IV hyperlipoproteinemia is commonly observed in association with coronary heart disease, non-Insulin-dependent (Type II) diabetes mellitus, obesity, alcoholism, and progestin therapy. Management relies on weight-reduction diets that replace simple sugars with complex carbohydrates, coupled with unsaturated fats and very low cholesterol intake. Hypolipidemic drugs are also utilized.

5. Familial hyperlipoproteinemia, Type V. In this condition, lipoprotein fraction alterations are highly complex, showing elevated levels of both chylomicrons and VLDL, resulting in marked hypertriacylglycerolemia and hypercholesterolemia, while LDL and HDL concentrations are depressed. Xanthomas frequently develop, though atherosclerosis does not always ensue. Impaired glucose tolerance often coexists with obesity and diabetes mellitus. The precise Etiology of this inherited disorder remains undetermined. Treatment focuses on weight management through a diet restricted in both carbohydrates and fats.

6. Familial hyperalphalipoproteinemia. This rare condition involves an elevated concentration of HDL, which is generally considered to confer cardiovascular protection and overall good health.

C. Familial Lecithin-Cholesterol Acyltransferase (LCAT) Deficiency

The blood plasma of patients shows low levels of esterified cholesterol and lysolecithin, while the concentrations of cholesterol and lecithin are elevated. The blood plasma is slightly turbid. Structural abnormalities in lipoproteins are also observed. One of the HDL fractions contains discoid structures arranged in rouleaux (“coin stacks”), which represent newly formed HDL incapable of incorporating cholesterol due to the absence of LCAT. There is also an LDL subfraction (lipoprotein-X), which under other conditions is detected only in patients with cholestasis (bile stasis). Furthermore, in this case, VLDL differ from normal ones: upon electrophoresis, they migrate as ß-lipoproteins (ß-VLDL). Patients with parenchymal liver damage also exhibit a decrease in LCAT activity and alterations in serum Lipids and lipoproteins.

Class="center">References

Brown М. S., Goldstein J. L. Lipoprotein metabolism in the macrophage: Implications for cholesterol deposition in atherosclerosis. Annu. Rev. Biochem., 1983, 52, 223.

Connor W. E., Connor S. L. The dietary treatment of hyperlipidemia, Med. Clin. North Am., 1982, 66, 485.

Eisenberg S. Lipoproteins and lipoprotein metabolism, Klin. Wochenschr., 1983. 61, 119.

Fears R., Sabine J. R. (eds) Cholesterol 7 a-Hydroxylase (7 a-Monooxygenase). CRC Press, 1986.

Fielding C. J., Fielding P. E. Metabolism of cholesterol and lipoproteins. Page 404 in: BIOCHEMISTRY OF LIPIDS and Membranes. Vance D. E., Vance J. E. (eds) Benjamin/Cummings. 1985.

Frohlich J., McLeod R., Hon K. Lecithin:cholesterol acyltransferase (LCAT), Clin. Biochem., 1982, 15, 269.

Kane J. P., Havel R. J. Treatment of hypercholesterolemia, Annu. Rev. Med., 1986, 37, 42.