Harpers

CHOLESTEROL SYNTHESIS, TRANSPORT, & EXCRETION / 223ATPREDUCTASEKINASE(inactive)PiREDUCTASEKINASEKINASEPPROTEINPHOSPHATASES+?InsulinADPREDUCTASEKINASE(active)H 2 O–Glucagon+HMG-CoALDL-cholesterolCholesterolOxysterols–ATPHMG-CoAREDUCTASE(active)PiEnzyme synthesisPROTEINPHOSPHATASESP?+–ADPHMG-CoAREDUCTASE(inactive)H 2 OInsulinInhibitor-1-phosphate*cAMP+Figure 26–4. Possible mechanisms in the regulation of cholesterol synthesis by HMG-CoA reductase. Insulinhas a dominant role compared with glucagon. Asterisk: See Figure 18–6.membrane; cholesterol synthesis; and hydrolysis of cholesterylesters by the enzyme cholesteryl ester hydrolase.Decrease is due to efflux of cholesterol from the membraneto HDL, promoted by LCAT (lecithin:cholesterolacyltransferase) (Chapter 25); esterification of cholesterolby ACAT (acyl-CoA:cholesterol acyltransferase); and utilizationof cholesterol for synthesis of other steroids, suchas hormones, or bile acids in the liver.The LDL Receptor Is Highly RegulatedLDL (apo B-100, E) receptors occur on the cell surfacein pits that are coated on the cytosolic side of the cellmembrane with a protein called clathrin. The glycoproteinreceptor spans the membrane, the B-100 bindingregion being at the exposed amino terminal end. Afterbinding, LDL is taken up intact by endocytosis. Theapoprotein and cholesteryl ester are then hydrolyzed inthe lysosomes, and cholesterol is translocated into thecell. The receptors are recycled to the cell surface. Thisinflux of cholesterol inhibits in a coordinated mannerHMG-CoA synthase, HMG-CoA reductase, and,therefore, cholesterol synthesis; stimulates ACAT activity;and down-regulates synthesis of the LDL receptor.Thus, the number of LDL receptors on the cell surfaceis regulated by the cholesterol requirement for membranes,steroid hormones, or bile acid synthesis (Figure26–5). The apo B-100, E receptor is a “high-affinity”LDL receptor, which may be saturated under most circumstances.Other “low-affinity” LDL receptors alsoappear to be present in addition to a scavenger pathway,which is not regulated.CHOLESTEROL IS TRANSPORTEDBETWEEN TISSUES IN PLASMALIPOPROTEINS(Figure 26–6)In Western countries, the total plasma cholesterol inhumans is about 5.2 mmol/L, rising with age, thoughthere are wide variations between individuals. Thegreater part is found in the esterified form. It is transportedin lipoproteins of the plasma, and the highestproportion of cholesterol is found in the LDL. Dietarycholesterol equilibrates with plasma cholesterol in days