Harpers

Cholesterol Synthesis,Transport,& Excretion 26Peter A. Mayes, PhD, DSc, & Kathleen M. Botham, PhD, DScBIOMEDICAL IMPORTANCECholesterol is present in tissues and in plasma either asfree cholesterol or as a storage form, combined with along-chain fatty acid as cholesteryl ester. In plasma,both forms are transported in lipoproteins (Chapter25). Cholesterol is an amphipathic lipid and as such isan essential structural component of membranes and ofthe outer layer of plasma lipoproteins. It is synthesizedin many tissues from acetyl-CoA and is the precursor ofall other steroids in the body such as corticosteroids, sexhormones, bile acids, and vitamin D. As a typical productof animal metabolism, cholesterol occurs in foodsof animal origin such as egg yolk, meat, liver, andbrain. Plasma low-density lipoprotein (LDL) is the vehicleof uptake of cholesterol and cholesteryl ester intomany tissues. Free cholesterol is removed from tissuesby plasma high-density lipoprotein (HDL) and transportedto the liver, where it is eliminated from the bodyeither unchanged or after conversion to bile acids in theprocess known as reverse cholesterol transport. Cholesterolis a major constituent of gallstones. However,its chief role in pathologic processes is as a factor in thegenesis of atherosclerosis of vital arteries, causing cerebrovascular,coronary, and peripheral vascular disease.CHOLESTEROL IS DERIVEDABOUT EQUALLY FROM THE DIET& FROM BIOSYNTHESISA little more than half the cholesterol of the body arisesby synthesis (about 700 mg/d), and the remainder isprovided by the average diet. The liver and intestine accountfor approximately 10% each of total synthesis inhumans. Virtually all tissues containing nucleated cellsare capable of cholesterol synthesis, which occurs in theendoplasmic reticulum and the cytosol.Acetyl-CoA Is the Source of All CarbonAtoms in CholesterolThe biosynthesis of cholesterol may be divided into fivesteps: (1) Synthesis of mevalonate occurs from acetyl-CoA (Figure 26–1). (2) Isoprenoid units are formedfrom mevalonate by loss of CO 2 (Figure 26–2). (3) Sixisoprenoid units condense to form squalene. (4) Squalenecyclizes to give rise to the parent steroid, lanosterol.(5) Cholesterol is formed from lanosterol (Figure26–3).Step 1—Biosynthesis of Mevalonate: HMG-CoA(3-hydroxy-3-methylglutaryl-CoA) is formed by the reactionsused in mitochondria to synthesize ketone bodies(Figure 22–7). However, since cholesterol synthesisis extramitochondrial, the two pathways are distinct.Initially, two molecules of acetyl-CoA condense toform acetoacetyl-CoA catalyzed by cytosolic thiolase.Acetoacetyl-CoA condenses with a further molecule ofacetyl-CoA catalyzed by HMG-CoA synthase to formHMG-CoA, which is reduced to mevalonate byNADPH catalyzed by HMG-CoA reductase. This isthe principal regulatory step in the pathway of cholesterolsynthesis and is the site of action of the most effectiveclass of cholesterol-lowering drugs, the HMG-CoAreductase inhibitors (statins) (Figure 26–1).Step 2—Formation of Isoprenoid Units: Mevalonateis phosphorylated sequentially by ATP by threekinases, and after decarboxylation (Figure 26–2) the activeisoprenoid unit, isopentenyl diphosphate, isformed.Step 3—Six Isoprenoid Units Form Squalene:Isopentenyl diphosphate is isomerized by a shift of thedouble bond to form dimethylallyl diphosphate, thencondensed with another molecule of isopentenyldiphosphate to form the ten-carbon intermediate geranyldiphosphate (Figure 26–2). A further condensationwith isopentenyl diphosphate forms farnesyldiphosphate. Two molecules of farnesyl diphosphatecondense at the diphosphate end to form squalene. Initially,inorganic pyrophosphate is eliminated, formingpresqualene diphosphate, which is then reduced byNADPH with elimination of a further inorganic pyrophosphatemolecule.Step 4—Formation of Lanosterol: Squalene canfold into a structure that closely resembles the steroidnucleus (Figure 26–3). Before ring closure occurs, squaleneis converted to squalene 2,3-epoxide by a mixed-219