Lipid disorders
1. What are the major lipids in the bloodstream?
Cholesterol and triglycerides (TGs) are the major circulating lipids. Cholesterol is used by all cells for the synthesis and repair of membranes and intracellular organelles and by the adrenal glands and gonads as a substrate to synthesize adrenal and gonadal steroid hormones. TGs are an energy source that can be stored as fat in adipose tissue or used as fuel by muscle and other tissues.
Cholesterol and TGs are not water soluble and thus cannot be transported through the circulation as individual molecules. Lipoproteins are large, spherical particles that package these lipids into a core surrounded by a shell of water-soluble proteins and phospholipids. Lipoproteins serve as vehicles that transport cholesterol and TGs from one part of the body to another.
3. What are the major lipoproteins in the bloodstream?
Chylomicrons, very-low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs) are the major circulating lipoproteins. Their functions are as follows:
| Chylomicrons | Transport exogenous TGs from the gut to adipose tissue and muscle |
| VLDLs | Transport endogenous TGs from the liver to adipose tissue and muscle |
| LDLs | Transport cholesterol from the liver to peripheral tissues |
| HDLs | Transport cholesterol from peripheral tissues to the liver |
4. What are the apolipoproteins?
Apolipoproteins are located on the surfaces of the lipoproteins. They function as ligands for binding to lipoprotein receptors and as cofactors for metabolic enzymes. Their functions are as follows:
| Apolipoprotein A | Ligand for peripheral HDL receptors |
| Apolipoprotein B | Ligand for peripheral LDL receptors |
| Apolipoprotein E | Ligand for hepatic receptors for remnant particles |
| Apolipoprotein C-II | Cofactor for lipoprotein lipase (LPL) |
5. Name other enzymes and transport proteins that are important in lipoprotein metabolism.
See Table 6-1 and Figure 6-1.
TABLE 6-1.
ENZYMES AND TRANSPORT PROTEINS IMPORTANT IN LIPOPROTEIN METABOLISM
| ENZYME/TRANSPORT PROTEIN | FUNCTION |
| Hydroxy-3-methyl-glutaryl-coenzyme A reductase | The rate-limiting enzyme in hepatic cholesterol synthesis |
| Lipoprotein lipase | Removes TGs from chylomicrons and VLDLs in adipose tissue, leaving remnant particles |
| Hepatic lipase | Removes additional TGs from remnant particles in the liver, converting them into LDLs |
| Lecithin cholesterol acyl transferase | Esterifies cholesterol molecules on the surface of HDLs, drawing them into the HDL core |
| Cholesterol ester transfer protein | Shuttles esterified cholesterol back and forth between HDLs and LDLs |
6. Explain the function and metabolism of TGs.
Food and hepatic synthesis are the major sources of TGs. They are transported by chylomicrons (dietary TGs) and VLDLs (endogenous TGs) to adipose tissue and muscle, where lipoprotein lipase and cofactor apolipoprotein C-II (Apo C-II) break down TGs into fatty acids (FAs) and monoglycerides. FAs enter adipose cells to be stored as fat or muscle cells to be used as fuel. The chylomicron and VLDL remnant particles return to the liver, where hepatic lipase converts VLDL remnants into LDL.
7. Describe the function and metabolism of LDL.
LDL transports cholesterol from the liver to peripheral tissues, where surface apolipoprotein B-100 binds to cellular LDL receptors (LDLRs). LDLR clustering in clathrin-coated pits on the cell membrane, promoted by LDLR adaptor protein-1 (LDLRAP1), is necessary for efficient LDL uptake. After LDL is internalized, it is degraded to free cholesterol (FC) for intracellular use. Excess LDL is cleared from the circulation by scavenger macrophages.
8. What is the function of HDL?
HDL removes excess cholesterol from cells by two mechanisms. Nascent pre-βHDL is made in the liver and intestine. Surface Apo A1 on pre-βHDL acquires FC through the adenosine triphosphate (ATP)–binding cassette (ABC) transporter-A1 (ABCA1) on arterial wall macrophages. Plasma lecithin cholesterol acyl transferase (LCAT) then esterifies the FC to cholesterol ester (CE). In addition, HDL accepts additional FC from arterial macrophages through the ABCG1 transporter and the scavenger receptor, class B, type 1 (SR-B1) receptor. Cholesterol ester transfer protein (CETP) transfers some CE back to LDL particles, and the mature HDL transports the remaining CE to the liver, where transfer occurs through hepatic SR-B1 receptors. In addition to performing reverse cholesterol transport, HDL reduces LDL oxidation, inhibits vascular inflammation, and improves endothelial function. All of these functions make HDL a potent antiatherogenic lipoprotein.
9. Describe the pathogenesis of the atherosclerotic plaque and arterial thrombosis.
LDL can be modified by oxidation. Scavenger macrophages located beneath the intimal surface of arteries engulf oxidized LDL, becoming lipid-laden foam cells, which secrete growth factors that stimulate smooth muscle cell proliferation. These developing plaques also secrete cytokines that attract inflammatory cells, which secrete proteolytic enzymes that erode the fibromuscular plaque cap, making it prone to rupture. When rupture occurs, platelets aggregate and release chemicals that promote vasoconstriction and initiate thrombus formation, which may ultimately occlude the artery.
10. Are elevated serum TG values harmful?
Increased serum TG levels are associated with atherosclerosis and increased coronary disease. The American Heart Association states that triglycerides are not directly atherogenic but represent an important biomarker of cardiovascular risk because of their association with an atherogenic lipid profile (low HDL cholesterol levels and small, dense LDL particles), as well as obesity, insulin resistance, and the metabolic syndrome. It has not yet been shown that decreasing TG levels will reduce coronary disease risk. TG values greater than 1000 mg/dL significantly increase the risk of acute pancreatitis.
11. What is metabolic syndrome?
Metabolic syndrome (MS) is a condition that is diagnosed when a patient has any three of the following findings: elevated fasting blood glucose (≥ 110 mg/dL), high TGs (≥ 150 mg/dL), low HDL (< 40 mg/dL for men, < 50 mg/dL for women), hypertension (≥ 130 mm Hg systolic/85 mm Hg diastolic), and abdominal obesity (waist > 40 inches in men, > 35 inches in women). The common thread among the disorders that constitute MS appears to be insulin resistance. MS carries a high risk for atherosclerotic vascular disease.
12. What is lipoprotein(a) [Lp(a)]?
Lipoprotein(a) [Lp(a)] has approximately 85% amino-acid sequence homology with plasminogen. When an Lp(a) molecule attaches to apoprotein B on the surface of an LDL particle, the new particle is referred to as Lp(a). Excessive Lp(a) promotes atherosclerosis, possibly because it is easily oxidized and engulfed by macrophages, because it inhibits thrombolysis, or both.
13. What are the primary dyslipidemias?
Primary dyslipidemias are inherited disorders of lipoprotein metabolism. The major primary dyslipidemias and their lipid phenotypes are as follows:
| PRIMARY DYSLIPIDEMIA | PHENOTYPE |
| Familial hypercholesterolemia (FH) | ↑↑Cholesterol |
| Polygenic hypercholesterolemia | ↑Cholesterol |
| Familial combined hyperlipidemia (FCH) | ↑Cholesterol and ↑TGs |
| Familial dysbetalipoproteinemia (FDL) | ↑Cholesterol and ↑TGs |
| Familial hypertriglyceridemia (FHT) | ↑TGs |
| Familial hyperchylomicronemia (FHC) | ↑↑TGs |
14. What is familial hypercholesterolemia?
FH is an inherited disease characterized by extreme elevations of serum cholesterol but normal serum TG levels. The disorder has a population frequency of 1:500 for heterozygotes, who generally have serum cholesterol levels of 300 to 800 mg/dL, and 1:1,000,000 for homozygotes, who have serum cholesterol levels of 600 to 1000 mg/dL. Most patients have genetic mutations resulting in deficient or dysfunctional LDL receptors (LDLRs). Other less common monogenic hypercholesterolemic disorders include apoprotein B mutations that produce a defective apo B that cannot bind to LDLR, proprotein convertase subtilisin–like kexin type 9 (PCSK9) mutations that cause accelerated LDLR degradation, LDLR adaptor protein-1 (LDLRAP1) mutations that prevent normal clustering of LDLR in cell surface clathrin-coated pits, and ATP-binding cassette G5 or G8 (ABCG5/8) mutations that cause abnormal cellular transport of cholesterol and plant sterols (sitosterolemia). These disorders are characterized by premature coronary artery disease (CAD), often before age 20 in homozygous FH, and tendon xanthomas.
15. What is familial combined hyperlipidemia?
FCH is an inherited disorder characterized by variable elevations of both serum cholesterol and TG. Affected patients have excessive hepatic apolipoprotein B synthesis, with increased numbers of apolipoprotein B–containing VLDL and LDL particles. The genetic basis for the disorder has not yet been determined. These patients are prone to development of premature CAD.
16. What is familial dysbetalipoproteinemia?
Familial dysbetalipoproteinemia (FDL), also known as broad beta disease, is an inherited condition characterized by significant and relatively balanced elevations of both serum cholesterol and TGs. This disorder results from an abnormal apolipoprotein E phenotype (E2/E2), which binds poorly to hepatic receptors, resulting in impaired clearance of circulating VLDL remnants by the liver. Affected patients often have premature CAD. Planar xanthomas in the creases of the palms and soles of the feet are a characteristic finding in patients with FDL.
17. What is polygenic hypercholesterolemia?
Polygenic hypercholesterolemia, which is characterized by mild to moderate elevations of serum cholesterol alone, is the most common type of inherited hypercholesterolemia. This condition generally occurs when one or more mild defects of cholesterol metabolism combine to elevate the serum cholesterol value. Affected patients have an increased risk of CAD.
18. What are familial hypertriglyceridemia and familial hyperchylomicronemia?
