Harpers

CHOLESTEROL SYNTHESIS, TRANSPORT, & EXCRETION / 229but raises HDL. Triacylglycerol concentrations are alsoreduced, due most likely to increased insulin sensitivity,which enhances expression of lipoprotein lipase.When Diet Changes Fail, HypolipidemicDrugs Will Reduce Serum Cholesterol& TriacylglycerolSignificant reductions of plasma cholesterol can be effectedmedically by the use of cholestyramine resin orsurgically by the ileal exclusion operations. Both proceduresblock the reabsorption of bile acids, causing increasedbile acid synthesis in the liver. This increasescholesterol excretion and up-regulates LDL receptors,lowering plasma cholesterol. Sitosterol is a hypocholesterolemicagent that acts by blocking the absorption ofcholesterol from the gastrointestinal tract.Several drugs are known to block the formation ofcholesterol at various stages in the biosynthetic pathway.The statins inhibit HMG-CoA reductase, thusup-regulating LDL receptors. Statins currently in useinclude atorvastatin, simvastatin, and pravastatin. Fibratessuch as clofibrate and gemfibrozil act mainly tolower plasma triacylglycerols by decreasing the secretionof triacylglycerol and cholesterol-containing VLDL bythe liver. In addition, they stimulate hydrolysis ofVLDL triacylglycerols by lipoprotein lipase. Probucolappears to increase LDL catabolism via receptorindependentpathways, but its antioxidant propertiesmay be more important in preventing accumulation ofoxidized LDL, which has enhanced atherogenic properties,in arterial walls. Nicotinic acid reduces the flux ofFFA by inhibiting adipose tissue lipolysis, thereby inhibitingVLDL production by the liver.Primary Disorders of the PlasmaLipoproteins (Dyslipoproteinemias)Are InheritedInherited defects in lipoprotein metabolism lead to theprimary condition of either hypo- or hyperlipoproteinemia(Table 26–1). In addition, diseases such asdiabetes mellitus, hypothyroidism, kidney disease(nephrotic syndrome), and atherosclerosis are associatedwith secondary abnormal lipoprotein patterns thatare very similar to one or another of the primary inheritedconditions. Virtually all of the primary conditionsare due to a defect at a stage in lipoprotein formation,transport, or destruction (see Figures 25–4, 26–5, and26–6). Not all of the abnormalities are harmful.SUMMARY• Cholesterol is the precursor of all other steroids inthe body, eg, corticosteroids, sex hormones, bileacids, and vitamin D. It also plays an importantstructural role in membranes and in the outer layer oflipoproteins.• Cholesterol is synthesized in the body entirely fromacetyl-CoA. Three molecules of acetyl-CoA formmevalonate via the important regulatory reaction forthe pathway, catalyzed by HMG-CoA reductase.Next, a five-carbon isoprenoid unit is formed, andsix of these condense to form squalene. Squalene undergoescyclization to form the parent steroid lanosterol,which, after the loss of three methyl groups,forms cholesterol.• Cholesterol synthesis in the liver is regulated partlyby cholesterol in the diet. In tissues, cholesterol balanceis maintained between the factors causing gainof cholesterol (eg, synthesis, uptake via the LDL orscavenger receptors) and the factors causing loss ofcholesterol (eg, steroid synthesis, cholesteryl ester formation,excretion). The activity of the LDL receptoris modulated by cellular cholesterol levels to achievethis balance. In reverse cholesterol transport, HDL(preβ-HDL, discoidal, or HDL 3 ) takes up cholesterolfrom the tissues and LCAT esterifies it and depositsit in the core of HDL, which is converted to HDL 2 .The cholesteryl ester in HDL 2 is taken up by theliver, either directly or after transfer to VLDL, IDL,or LDL via the cholesteryl ester transfer protein.• Excess cholesterol is excreted from the liver in thebile as cholesterol or bile salts. A large proportion ofbile salts is absorbed into the portal circulation andreturned to the liver as part of the enterohepatic circulation.• Elevated levels of cholesterol present in VLDL, IDL,or LDL are associated with atherosclerosis, whereashigh levels of HDL have a protective effect.• Inherited defects in lipoprotein metabolism lead to aprimary condition of hypo- or hyperlipoproteinemia.Conditions such as diabetes mellitus, hypothyroidism,kidney disease, and atherosclerosis exhibitsecondary abnormal lipoprotein patterns that resemblecertain primary conditions.REFERENCESIllingworth DR: Management of hypercholesterolemia. Med ClinNorth Am 2000;84:23.Ness GC, Chambers CM: Feedback and hormonal regulation ofhepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase:the concept of cholesterol buffering capacity. Proc Soc ExpBiol Med 2000;224:8.Parks DJ et al: Bile acids: natural ligands for a nuclear orphan receptor.Science 1999;284:1365.Princen HMG: Regulation of bile acid synthesis. Curr Pharm Design1997;3:59.