clinical significans of hyperlipidemia

Clinical Significances of Lipoprotein Metabolism

Fortunately, few individuals carry the inherited defects in lipoprotein metabolism that lead to hyper- or hypolipoproteinemias (see Tables below for brief descriptions). Persons suffering from diabetes mellitus, hypothyroidism and kidney disease often exhibit abnormal lipoprotein metabolism as a result of secondary effects of their disorders. For example, because lipoprotein lipase (LPL) synthesis is regulated by insulin, LPL deficiencies leading to Type I hyperlipoproteinemia may occur as a secondary outcome of diabetes mellitus. Additionally, insulin and thyroid hormones positively affect hepatic LDL-receptor interactions; therefore, the hypercholesterolemia and increased risk of athersclerosis associated with uncontrolled diabetes or hypothyroidism is likely due to decreased hepatic LDL uptake and metabolism.

Of the many disorders of lipoprotein metabolism, familial hypercholesterolemia (FH) may be the most prevalent in the general population. Heterozygosity at the FH locus occurs in 1:500 individuals, whereas, homozygosity is observed in 1:1,000,000 individuals. FH is an inherited disorder comprising four different classes of mutation in the LDL receptor gene. The class 1 defect (the most common) results in a complete loss of receptor synthesis. The class 2 defect results in the synthesis of a receptor protein that is not properly processed in the Golgi apparatus and therefore is not transported to the plasma membrane. The class 3 defect results in an LDL receptor that is incapable of binding LDLs. The class 4 defect results in receptors that bind LDLs but do not cluster in coated pits and are, therefore, not internalized.

FH sufferers may be either heterozygous or homologous for a particular mutation in the receptor gene. Homozygotes exhibit grossly elevated serum cholesterol (primarily in LDLs). The elevated levels of LDLs result in their phagocytosis by macrophages. These lipid-laden phagocytic cells tend to deposit within the skin and tendons, leading to xanthomas. A greater complication results from cholesterol deposition within the arteries, leading to atherosclerosis, the major contributing factor of nearly all cardiovascular diseases.
back to the top
Hyperlipoproteinemias
Disorder

Defect

Comments
Type I
(familial LPL deficiency, familial hyperchylomicronemia) (a) deficiency of LPL;
(b) production of abnormal LPL;
(c) apoC-II deficiency slow chylomicron clearance, reduced LDL and HDL levels; treated by low fat/complex carbohydrate diet; no increased risk of coronary artery disease
Type II
(familial hypercholesterolemia, FH) 4 classes of LDL receptor defect reduced LDL clearance leads to hypercholesterolemia, resulting in athersclerosis and coronary artery disease
Type III
(familial dysbetalipoproteinemia, remnant removal disease, broad beta disease, apolipoprotein E deficiency) hepatic remnant clearance impaired due to apoE abnormality; patients only express the apoE2 isoform that interacts poorly with the apoE receptor causes xanthomas, hypercholesterolemia and athersclerosis in peripheral and coronary arteries due to elevated levels of chylomicrons and VLDLs
Type IV
(familial hypertriacylglycerolemia) elevated production of VLDL associated with glucose intolerance and hyperinsulinemia frequently associated with type-II non-insulin dependent diabetes mellitus, obesity, alcoholism or administration of progestational hormones; elevated cholesterol as a result of increased VLDLs
Type V familial elevated chylomicrons and VLDLs due to unknown cause hypertriacylglycerolemia and hypercholesterolemia with decreased LDLs and HDLs
Familial hyperalphalipoproteinemia increased level of HDLs a rare condition that is beneficial for health and longevity
Type II
Familial hyperbetalipoproteinemia increased LDL production and delayed clearance of triacylglycerols and fatty acids strongly associated with increased risk of coronary artery disease
Familial ligand-defective apoB 2 different mutations: Gln for Arg (amino acid 3500) or Cys for Arg (amino acid 3531); both lead to reduced affinity of LDL for LDL receptor dramatic increase in LDL levels; no affect on HDL, VLDL or plasma triglyceride levels; significant cause of hypercholesterolemia and premature coronary artery disease
Familial LCAT deficiency absence of LCAT leads to inability of HDLs to take up cholesterol
(reverse cholesterol transport) decreased levels of plasma cholesteryl esters and lysolecithin; abnormal LDLs (Lp-X) and VLDLs; symptoms also found associated with cholestasis
Wolman disease
(cholesteryl ester storage disease) defect in lysosomal cholesteryl ester hydrolase; affects metabolism of LDLs reduced LDL clearance leads to hypercholesterolemia, resulting in athersclerosis and coronary artery disease
heparin-releasable hepatic triglyceride lipase deficiency deficiency of the lipase leads to accumulation of triacylglycerol-rich HDLs and VLDL remnants (IDLs) causes xanthomas and coronary artery disease

back to the top
Hypolipoproteinemias
Disorder Defect Comments
Abetalipoproteinemia
(acanthocytosis, Bassen-Kornzweig syndrome) no chylomicrons, VLDLs or LDLs due to defect in apoB expression rare defect; intestine and liver accumulate, malabsorption of fat, retinitis pigmentosa, ataxic neuropathic disease, erythrocytes have thorny appearance
Familial hypobetalipoproteinemia at least 20 different apoB gene mutations identified, LDL concentrations 10-20% of normal, VLDL slightly lower, HDL normal mild or no pathological changes
Familial alpha-lipoprotein deficiency
(Tangier disease, Fish-eye disease, apoA-I and -C-III deficiencies) all of these related syndromes have reduced HDL concentrations, no effect on chylomicron or VLDL production tendency to hypertriacylglycerolemia; some elevation in VLDLs; Fish-eye disease characterized by severe corneal opacity

back to the top
Pharmacologic Intervention

Drug treatment to lower plasma lipoproteins and/or cholesterol is primarily aimed at reducing the risk of athersclerosis and subsequent coronary artery disease that exists in patients with elevated circulating lipids. Drug therapy usually is considered as an option only if non-pharmacologic interventions (altered diet and exercise) have failed to lower plasma lipids.

Atorvastatin (Lipotor®), Simvastatin (Zocor®), Lovastatin (Mevacor®): These drugs are fungal HMG-CoA reductase (HMGR) inhibitors and are members of the family of drugs referred to as the statins. The net result of treatment is an increased cellular uptake of LDLs, since the intracellular synthesis of cholesterol is inhibited and cells are therefore dependent on extracellular sources of cholesterol. However, since mevalonate (the product of the HMG-CoA reductase reaction) is required for the synthesis of other important isoprenoid compounds besides cholesterol, long-term treatments carry some risk of toxicity.

The statins have become recognized as a class of drugs capable of more pharmacologic benefits than just lowering blood cholesterol levels via their actions on HMGR. Part of the cardiac benefit of the statins relates to their ability to regulate the production of S-nitrosylated COX-2. COX-2 is an inducible enzyme involved in the synthesis of the prostaglandins and thromboxanes as well as the lipoxins and resolvins. The latter two classes of compounds are anti-inflammatory lipids discussed in the Aspirin page. Evidence has shown that statins activate inducible nitric oxide synthase (iNOS) leading to nitrosylation of COX-2. The S-nitrosylated COX-2 enzyme produces the lipid compound 15R-hydroxyeicosatetraenoic acid (15R-HETE) which is then converted via the action of 5-lipoxygenase (5-LOX) to the epimeric lipoxin, 15-epi-LXA4. This latter compound is the same as the aspirin-triggered lipoxin (ATL) that results from the aspirin-induced acetylation of COX-2. Therefore, part of the beneficial effects of the statins are exerted via the actions of the lipoxin family of anti-inflammatory lipids.

Nicotinic acid: Nicotinic acid reduces the plasma levels of both VLDLs and LDLs by inhibiting hepatic VLDL secretion, as well as suppressing the flux of FFA release from adipose tissue by inhibiting lipolysis. Because of its ability to cause large reductions in circulating levels of cholesterol, nicotinic acid is used to treat Type II, III, IV and V hyperlipoproteinemias.

Gemfibrozil (Lopid®), Fenofibrate (TriCor®): These compounds (called fibrates) are derivatives of fibric acid and although used clinically since the 1930's were only recently discovered to exert some of their lipid-lowering effects via the activation of peroxisome proliferation. Specifically, the fibrates were found to be activators of the peroxisome proliferator-activated receptor-α (PPAR-α) class of proteins that are classified as co-activators. The naturally occurring ligands for PPAR-α are leukotriene B4 (LTB4, see the Lipid Synthesis page), unsaturated fatty acids and oxidized components of VLDLs and LDLs. The PPARs interact with another receptor family called the retinoid X receptors (RXRs) that bind 9-cis-retinoic acid. Activation of PPARs results in modulation of the expression of genes involved in lipid metabolism. In addition the PPARs modulate carbohydrate metabolism and adipose tissue differentiation. Fibrates result in the activation of PPAR-α in liver and muscle. In the liver this leads to increased β-oxidation of fatty acids, thereby decreasing the liver's secretion of triacylglycerol- and cholesterol-rich VLDLs, as well as increased clearance of chylomicron remnants, increased levels of HDLs and increased lipoprotein lipase activity which in turn promotes rapid VLDL turnover.

Cholestyramine or colestipol (resins): These compounds are nonabsorbable resins that bind bile acids which are then not reabsorbed by the liver but excreted. The drop in hepatic reabsorption of bile acids releases a feedback inhibitory mechanism that had been inhibiting bile acid synthesis. As a result, a greater amount of cholesterol is converted to bile acids to maintain a steady level in circulation. Additionally, the synthesis of LDL receptors increases to allow increased cholesterol uptake for bile acid synthesis, and the overall effect is a reduction in plasma cholesterol. This treatment is ineffective in homozygous FH patients, since they are completely deficient in LDL receptors.