Harper's Biochemistry: Cholesterol Synthesis, Transport, & Excretion PDF

C H A P T E R Cholesterol Synthesis, Transport, & Excretion Kathleen M. Botham, PhD, DSc, & Peter A. Mayes, PhD, DSc 26 O B J E C TI V E S Explain the importance o...

C H A P T E R Cholesterol Synthesis, Transport, & Excretion Kathleen M. Botham, PhD, DSc, & Peter A. Mayes, PhD, DSc 26 O B J E C TI V E S Explain the importance of cholesterol as an essential structural component of cell membranes and as a precursor of all other steroids in the body, and After studying this chapter, indicate its pathologic role in cholesterol gallstone disease and atherosclerosis you should be able to: development. Identify the five stages in the biosynthesis of cholesterol from acetyl-CoA. Indicate the role of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) in controlling the rate of cholesterol synthesis and explain the mechanisms by which its activity is regulated. Explain that cholesterol balance in cells is tightly regulated and indicate the factors involved in maintaining the correct balance. Explain the role of plasma lipoproteins, including chylomicrons, very-low- density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), in the transport of cholesterol between tissues in the plasma. Name the two main primary bile acids found in mammals and outline the pathways by which they are synthesized from cholesterol in the liver. Explain the importance of bile acid synthesis not only in the digestion and absorption of fats but also as a major excretory route for cholesterol. Indicate how secondary bile acids are produced from primary bile acids by intestinal bacteria. Explain what is meant by the “enterohepatic circulation” and why it is important. Identify various factors related to plasma cholesterol concentrations that affect the risk of coronary heart disease, including diet and lifestyle and the class of lipoprotein in which it is carried. Give examples of inherited and noninherited conditions affecting lipoprotein metabolism that cause hypo- or hyperlipoproteinemia. BIOMEDICAL IMPORTANCE other steroids in the body, including corticosteroids, sex hor- mones, bile acids, and vitamin D. As a typical product of ani- Cholesterol is present in tissues and in plasma either as free mal metabolism, cholesterol occurs in foods of animal origin cholesterol or combined with a long-chain fatty acid as cho- such as egg yolk, meat, liver, and brain. Plasma low-density lesteryl ester, the storage form. In plasma, both forms are lipoprotein (LDL) is the vehicle that supplies cholesterol and transported in lipoproteins (see Chapter 25). Cholesterol is an cholesteryl ester to many tissues. Free cholesterol is removed amphipathic lipid and as such is an essential structural com- from tissues by plasma high-density lipoprotein (HDL) and ponent of membranes, where it is important for the mainte- transported to the liver, where it is eliminated from the body nance of the correct permeability and fluidity (see Chapter 40), either unchanged or after conversion to bile acids in the pro- and of the outer layer of plasma lipoproteins. It is synthesized cess known as reverse cholesterol transport (see Chapter 25). in many tissues from acetyl-CoA and is the precursor of all 259 260 SECTION V Metabolism of Lipids Cholesterol is a major constituent of gallstones. However, its O chief role in pathologic processes is as a factor in the develop- CH3 C S CoA ment of atherosclerosis of vital arteries, causing cerebrovas- 2 Acetyl-CoA cular, coronary, and peripheral vascular disease. Thiolase CoA SH CH3 O CHOLESTEROL IS C CH2 C S CoA BIOSYNTHESIZED O Acetoacetyl-CoA O FROM ACETYL-CoA H2O CH3 C S CoA C A little more than half the cholesterol of the body arises by Acetyl-CoA HMG-CoA synthase synthesis (about 700 mg/d), and the remainder is provided by CoA SH the average diet. The liver and intestine account for approxi- CH3 O mately 10% each of total synthesis in humans. Virtually all –OOC tissues containing nucleated cells are capable of cholesterol CH2 C C CH2 C S CoA synthesis, which occurs in the endoplasmic reticulum and the OH cytosolic compartments. 3-Hydroxy-3-methylglutaryl-CoA o (HMG-CoA) Bile acid, cholesterol 2NADPH + 2H+ Acetyl-CoA Is the Source of All HMG-CoA reductase Statins, eg, simvastatin Carbon Atoms in Cholesterol 2NADP+ + CoA SH Mevalonate Cholesterol is a 27-carbon compound consisting of four rings CH3 and a side chain (see Figure 21–19). It is synthesized from acetyl- – OOC CH2 C CH2 CH2 OH CoA by a lengthy pathway that may be divided into five steps: OH (1) synthesis of mevalonate from acetyl-CoA (Figure 26–1); Mevalonate (2) formation of isoprenoid units from mevalonate by loss of CO2 (Figure 26–2); (3) condensation of six isoprenoid units FIGURE 26–1 Biosynthesis of mevalonate. HMG-CoA reduc- tase is inhibited by statins. The open and solid circles indicate the fate form squalene (see Figure 26–2); (4) cyclization of squalene gives of each of the carbons in the acetyl moiety of acetyl-CoA. rise to the parent steroid, lanosterol (Figure 26–3); (5) formation of cholesterol from lanosterol (see Figure 26–3). Step 1—Biosynthesis of Mevalonate:HMG-CoA (3-hydroxy- 3-methylglutaryl-CoA) is formed by the reactions used in at the diphosphate end to form squalene. Initially, inorganic mitochondria to synthesize ketone bodies (see Figure 22–7). pyrophosphate is eliminated, forming presqualene diphosphate, However, since cholesterol synthesis is extramitochondrial, the which is then reduced by NADPH with elimination of a further two pathways are distinct. Initially, two molecules of acetyl- inorganic pyrophosphate molecule. Farnesyl diphosphate is CoA condense to form acetoacetyl-CoA catalyzed by cytosolic also an intermediate in the formation of other important com- thiolase. Acetoacetyl-CoA condenses with a further molecule pounds which contain isoprenoid units such as dolichol and of acetyl-CoA catalyzed by HMG-CoA synthase to form ubiquinone (see following discussion and Figure 26–2). HMG-CoA, which is reduced to mevalonate by NADPH in Step 4—Formation of Lanosterol: Squalene can fold a reaction catalyzed by HMG-CoA reductase. This last step into a structure that closely resembles the steroid nucleus is the principal regulatory step in the pathway of cholesterol (see Figure 26–3). Before ring closure occurs, squalene is synthesis and is the site of action of the most effective class of converted to squalene 2,3-epoxide by squalene epoxidase, cholesterol-lowering drugs, the statins, which are HMG-CoA a mixed-function oxidase in the endoplasmic reticulum. The reductase inhibitors (see Figure 26–1). methyl group on C14 is transferred to C13 and that on C8 to C14 Step 2—Formation of Isoprenoid Units: Mevalonate is as cyclization occurs, catalyzed by oxidosqualene-lanosterol phosphorylated sequentially using ATP by three kinases, and cyclase. after decarboxylation (see Figure 26–2) of the active isoprenoid Step 5—Formation of Cholesterol: The formation of unit, isopentenyl diphosphate, is formed. cholesterol from lanosterol takes place in the membranes of Step 3—Six Isoprenoid Units Form Squalene: Isopentenyl the endoplasmic reticulum and involves changes in the ste- diphosphate is isomerized by a shift of the double bond to form roid nucleus and the side chain (see Figure 26–3). The methyl dimethylallyl diphosphate, and then condensed with another groups on C14 and C4 are removed to form 14-desmethyl lanos- molecule of isopentenyl diphosphate to form the 10-carbon terol and then zymosterol. The double bond at C8—C9 is sub- intermediate geranyl diphosphate (see Figure 26–2). A fur- sequently moved to C5—C6 in two steps, forming desmosterol ther condensation with isopentenyl diphosphate forms farnesyl (24-dehydrocholesterol). Finally, the double bond of the side diphosphate. Two molecules of farnesyl diphosphate condense chain is reduced, producing cholesterol.  CHAPTER 26 Cholesterol Synthesis, Transport, & Excretion 261 ATP ADP CH3 OH CH3 OH Mg2+ – – OOC C CH2 OOC C CH2 Mevalonate CH2 CH2 OH kinase CH2 CH2 O P Mevalonate Mevalonate 5-phosphate ATP Phosphomevalonate Mg2+ kinase ADP ADP ATP CH3 O P CH3 OH Mg2+ – – OOC C CH2 OOC C CH2 Diphosphomevalonate CH2 CH2 O P P kinase CH2 CH2 O P P Mevalonate 3-phospho-5-diphosphate Mevalonate 5-diphosphate CO2 + Pi Diphospho- mevalonate CH3 decarboxylase CH3 C CH2 C CH2 CH3 CH O P P Isopentenyl- CH2 CH2 O P P diphosphate 3,3-Dimethylallyl lsomerase Isopentenyl diphosphate diphosphate cis-Prenyl transferase PPi CH3 CH3 C CH2 C C CH2 Prenylated proteins CH3 CH CH2 CH O P P Geranyl diphosphate cis-Prenyl transferase PPi trans-Prenyl cis-Prenyl transferase transferase Side chain of * 2 CH Dolichol ubiquinone O P P Farnesyl diphosphate NADPH + H+ Squalene synthetase Mg2+, Mn2+ 2PPi NADP+ * 2 CH *CH2 Squalene FIGURE 26–2 Biosynthesis of squalene, ubiquinone, dolichol, and other polyisoprene derivatives. (HMG, 3-hydroxy-3-methylglutaryl.) A farnesyl residue is present in heme of a cytochrome oxidase. The carbon marked with an asterisk becomes C11 or C12 in squalene. The open circles indicate the origin of the PPi eliminated in the formation of geranyl diphosphate. Squalene synthetase is a microsomal enzyme; all other enzymes indicated are soluble cytosolic proteins, and some are found in peroxisomes. Farnesyl Diphosphate Gives Rise to from farnesyl diphosphate by the further addition of up to 16 (dolichol) or 3 to 7 (ubiquinone) isopentenyl diphosphate Dolichol & Ubiquinone residues (see Figure 26–2). Some GTP-binding proteins in The polyisoprenoids, dolichol (see Figure 21–22 and the cell membrane are prenylated with farnesyl or geranyl- Chapter 46) and ubiquinone (see Figure 13–6) are formed geranyl (20 carbon) residues. Protein prenylation is believed 262 SECTION V Metabolism of Lipids O CH3 CH3 –OOC CH3 C S CoA CH2 C CH2 CH2OH CH3 C CH CH2– OH CO2 H2O Acetyl-CoA Mevalonate Isoprenoid unit CH3 CH2 CH3 CH2 C CH2 C CH2 12 12 24 CH3 24 CH3 CH2 13 CH HC C * CH2 13 CH HC C Squalene 11 CH3 11 * CH3 epoxide CH2 CH CH2 CH2 CH CH2 1 CH3 1 CH3 CH2 CH 14 C CH2 CH2 CH 14 C CH2 8 Squalene 8 H2C C C CH3 epoxidase H2C C C CH3 CH3 CH3 3 NADPH 3 X6 HC CH CH2 1/2 O2 HC CH CH2 FAD C CH2 C CH2 Squalene O Oxidosqualene: CH3 lanosterol CH3 CH3 CH3 cyclase H COOH 2CO2 14 14 8 NADPH O2, NADPH 8 O2 NAD+ 4 HO HO HO Lanosterol 14-Desmethyl Zymosterol lanosterol Isomerase 21 22 18 20 23 26 24 25 24 24 12 17 NADPH NADPH 19 11 13 16 27 C D 15 14 O2 2 1 10 9 8 24-Reductase A B 3 5 7 3 7 4 6 5 HO HO HO 7,24 Cholesterol Desmosterol  -Cholestadienol (24-dehydrocholesterol) FIGURE 26–3 Biosynthesis of cholesterol. The numbered positions are those of the steroid nucleus and the open and solid circles indi- cate the fate of each of the carbons in the acetyl moiety of acetyl-CoA. (*Refer to labeling of squalene in Figure 26–2.) to facilitate the anchoring of proteins into lipoid membranes Regulatory mechanisms include both modulation of the syn- and may also be involved in protein–protein interactions and thesis of enzyme protein and posttranslational modification. membrane-associated protein trafficking. Cholesterol and metabolites repress transcription of HMG- CoA reductase mRNA via inhibition of a sterol regulatory element-binding protein (SREBP) transcription factor. CHOLESTEROL SYNTHESIS IS SREBPs are a family of proteins that regulate the transcrip- CONTROLLED BY REGULATION tion of a range of genes involved in the cellular uptake and metabolism of cholesterol and other lipids. SREBP activation OF HMG-CoA REDUCTASE is inhibited by insulin-induced gene (Insig), a protein whose Cholesterol synthesis is tightly controlled by regulation at expression, as its name indicates, is induced by insulin and is the HMG-CoA reductase step. The activity of the enzyme is present in the endoplasmic reticulum. Insig also promotes deg- inhibited by mevalonate, the immediate product of the reac- radation of HMG-CoA reductase. A diurnal variation occurs tion, and by cholesterol, the main product of the pathway. both in cholesterol synthesis and reductase activity. Short- Thus, increased intake of cholesterol from the diet leads term changes in enzyme activity, however, are brought about to a decrease in de novo synthesis, especially in the liver. by posttranslational modification (Figure 26–4). Insulin or  CHAPTER 26 Cholesterol Synthesis, Transport, & Excretion 263 AMPK (inactive) ATP Pi + Insulin AMPKK Protein ? phosphatases AMP P – Glucagon ADP AMPK (active) H2O + ATP ADP Inhibitor-1- cAMP phosphate* + HMG-CoA LDL-cholesterol HMG-CoA HMG-CoA reductase P reductase (active) (inactive) Cholesterol H2O ? Insulin Pi + – Oxysterols Protein phosphatases – Gene transcription FIGURE 26–4 Possible posttranslational mechanisms in the regulation of cholesterol synthesis by HMG-CoA reductase. Insulin has a dominant role compared with glucagon. Stimulatory ( ) or inhibitory () effects are shown as dotted green or red arrows, respectively. (AMPK, AMP-activated protein kinase; AMPKK, AMP-activated protein kinase kinase.) *See Figure 18–6. thyroid hormone increases HMG-CoA reductase activity, other steroids, such as hormones, in steroidogenic tissues, or whereas glucagon or glucocorticoids decrease it. Activity is bile acids in the liver. reversibly modified by phosphorylation–dephosphorylation mechanisms, some of which may be cAMP-dependent and therefore immediately responsive to glucagon. AMP-activated The LDL Receptor Plays an Important protein kinase (AMPK) (formerly called HM-CoA reductase Role in the Maintenance of Intracellular kinase) phosphorylates and inactivates HMG-CoA reductase. Cholesterol Balance AMPK is activated via phosphorylation by AMPK kinase LDL (apo B-100, E) receptors occur on the cell surface in pits (AMPKK) and by allosteric modification by AMP. that are coated on the cytosolic side of the cell membrane with a protein called clathrin. The glycoprotein receptor spans the THE CHOLESTEROL BALANCE IN membrane, the B-100 binding region being at the exposed amino terminal end. After binding, LDL is taken up intact by TISSUES IS TIGHTLY REGULATED endocytosis. The apoprotein and cholesteryl ester are then In tissues, a tight balance must be maintained between those hydrolyzed in the lysosomes, and cholesterol is translocated factors which increase cholesterol levels and those which into the cell. The receptors are recycled to the cell surface. decrease them, thus keeping intracellular concentrations This influx of cholesterol inhibits the transcription of the constant (Figure 26–5). An increase in cell cholesterol may genes encoding HMG-CoA synthase, HMG-CoA reductase, be caused by: (1) Uptake of cholesterol-containing lipopro- and other enzymes involved in cholesterol synthesis, as well teins by receptors, for example, the LDL receptor or scavenger as the LDL receptor itself, via the SREBP pathway, and thus receptors such as CD36. (2) Uptake of free cholesterol from coordinately suppresses cholesterol synthesis and uptake. cholesterol-rich lipoproteins to the cell membrane. (3) Cho- ACAT activity is also stimulated, promoting cholesterol esteri- lesterol synthesis. (4) Hydrolysis of cholesteryl esters by the fication. In addition, recent research has shown that the pro- enzyme cholesteryl ester hydrolase. A decrease may be due tein proprotein convertase subtilisin/kexin type 9 (PCSK9) to: (1) Efflux of cholesterol from the membrane to HDL via regulates the recycling of the receptor to the cell surface by the ABCA1, ABCG1, or SR-B1 (see Figure 25–5). (2) Esteri- targeting it for degradation. By these mechanisms, LDL recep- fication of cholesterol by ACAT (acyl-CoA:cholesterol acyl- tor activity on the cell surface is regulated by the cholesterol transferase). (3) Utilization of cholesterol for synthesis of requirement for membranes, steroid hormones, or bile acid 264 SECTION V Metabolism of Lipids FIGURE 26–5 Factors affecting cholesterol balance at the cellular level. Reverse cholesterol transport may be mediated via the ABCA1 transporter protein (with preβ-HDL as the exogenous acceptor) or the SR-B1 or ABCG1 (with HDL 3 as the exogenous acceptor). Stimulatory ( ) or inhibitory () effects are shown as dotted green or red arrows, respectively. (ACAT, acyl-CoA:cholesterol acyltransferase; A-I, apolipoprotein A-I; C, cholesterol; CE, cholesteryl ester; LCAT, lecithin:cholesterol acyltransferase; LDL, low-density lipoprotein; PL, phospholipid; VLDL, very-low-density lipoprotein.) LDL and HDL are not shown to scale. synthesis, and the free cholesterol content of the cell is kept Plasma LCAT Is Responsible for within relatively narrow limits (see Figure 26–5). Virtually All Plasma Cholesteryl Ester in Humans CHOLESTEROL IS TRANSPORTED Lecithin: cholesterol acyltransferase (LCAT) activity is asso- BETWEEN TISSUES IN PLASMA ciated with HDL containing apo A-I. As cholesterol in HDL LIPOPROTEINS becomes esterified, it creates a concentration gradient and draws in cholesterol from tissues and from other lipoproteins Cholesterol is transported in plasma in lipoproteins (see (see Figures 26–5 and 26–6), thus enabling HDL to function in Table 25–1), with the greater part in the form of cholesteryl reverse cholesterol transport (see Figure 25–5). ester (Figure 26–6), and in humans the highest proportion is found in LDL. Dietary cholesterol equilibrates with plasma cholesterol in days and with tissue cholesterol in weeks. Cho- Cholesteryl Ester Transfer Protein lesteryl ester in the diet is hydrolyzed to cholesterol, which is then absorbed by the intestine together with dietary unesteri- Facilitates Transfer of Cholesteryl Ester fied cholesterol and other lipids. With cholesterol synthesized From HDL to Other Lipoproteins in the intestines, it is then incorporated into chylomicrons (see Cholesteryl ester transfer protein, associated with HDL, is Chapter 25). Of the cholesterol absorbed, 80 to 90% is esterified found in plasma of humans and many other species. It facili- with long-chain fatty acids in the intestinal mucosa. Ninety-five tates transfer of cholesteryl ester from HDL to VLDL, IDL, percent of the chylomicron cholesterol is delivered to the liver and LDL in exchange for triacylglycerol, relieving product in chylomicron remnants, and most of the cholesterol secreted inhibition of the LCAT activity in HDL. Thus, in humans, by the liver in very-low-density lipoprotein (VLDL) is retained much of the cholesteryl ester formed by LCAT finds its way to during the formation of intermediate-density lipoprotein (IDL) the liver via VLDL remnants (IDL) or LDL (see Figure 26–6). and ultimately LDL, which is taken up by the LDL receptor in The triacylglycerol-enriched HDL2 delivers its cholesterol to liver and extrahepatic tissues (see Chapter 25). the liver in the HDL cycle (see Figure 25–5).  CHAPTER 26 Cholesterol Synthesis, Transport, & Excretion 265 LDL (apo B-100, E) receptor) A-I LDL (apo B-100, E) receptor) FIGURE 26–6 Transport of cholesterol between the tissues in humans. ACAT, acyl-CoA:cholesterol acyltransferase; A-I, apolipoprotein A-I; C, unesterified cholesterol; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; HL, hepatic lipase; IDL, intermediate-density lipoprotein; LCAT, lecithin:cholesterol acyltransferase; LDL, low-density lipoprotein; LPL, lipoprotein lipase; LRP, LDL receptor–related protein-1; TG, triacylglycerol; VLDL, very-low-density lipoprotein. CHOLESTEROL IS EXCRETED P450. Subsequent hydroxylation steps are also catalyzed by monooxygenases. The pathway of bile acid biosynthesis divides FROM THE BODY IN THE BILE AS early into one subpathway leading to cholyl-CoA, characterized CHOLESTEROL OR AS BILE ACIDS by an extra α-OH group on position 12, and another pathway Cholesterol is excreted from the body via the bile either in leading to chenodeoxycholyl-CoA (see Figure 26–7). A sec- the unesterified form or after conversion into bile acids in ond pathway in mitochondria involving the 27-hydroxylation the liver. Coprostanol is the principal sterol in the feces; it is of cholesterol by the cytochrome P450 sterol 27-hydroxylase formed from cholesterol by the bacteria in the lower intestine. (CYP27A1) as the first step is responsible for a significant pro- portion of the primary bile acids synthesized. The primary bile acids (see Figure 26–7) enter the bile as glycine or taurine conju- Bile Acids Are Formed from Cholesterol gates. Conjugation takes place in liver peroxisomes. In humans, The primary bile acids are synthesized in the liver from cho- the ratio of the glycine to the taurine conjugates is normally 3:1. lesterol. These are cholic acid (found in the largest amount in The anions of the bile acids and their glyco- or tauro- conjugates most mammals) and chenodeoxycholic acid (Figure 26–7). are termed bile salts, and in the alkaline bile (pH 7.6-8.4), they The 7α-hydroxylation of cholesterol is the first and principal are assumed to be in this form. regulatory step in the biosynthesis of bile acids and is catalyzed Primary bile acids are further metabolized in the intestine by cholesterol 7α-hydroxylase, a microsomal cytochrome by the activity of the intestinal bacteria. Thus, deconjugation P450 enzyme–designated CYP7A1 (see Chapter 12). A typical and 7α-dehydroxylation occur, producing the secondary bile monooxygenase, it requires oxygen, NADPH, and cytochrome acids, deoxycholic acid, and lithocholic acid (see Figure 26–7). 266 SECTION V Metabolism of Lipids FIGURE 26–7 Biosynthesis and degradation of bile acids. A second pathway in mitochondria involves hydroxylation of cholesterol by sterol 27-hydroxylase. *Catalyzed by microbial enzymes. Most Bile Acids Return to the Liver in acids of constant size is maintained. This is accomplished by a system of feedback controls. the Enterohepatic Circulation Although products of fat digestion, including cholesterol, are absorbed in the first 100 cm of small intestine, the primary Bile Acid Synthesis Is Regulated and secondary bile acids are absorbed almost exclusively in the at the CYP7A1 Step ileum, and 98 to 99% is returned to the liver via the portal cir- The principal rate-limiting step in the biosynthesis of bile acids culation. This is known as the enterohepatic circulation (see is at the CYP7A1 reaction (see Figure 26–7). The activity of Figure 26–6). However, lithocholic acid, because of its insolu- the enzyme is feedback regulated via the nuclear bile acid– bility, is not reabsorbed to any significant extent. Only a small binding receptor, farnesoid X receptor (FXR). When the size fraction of the bile acids escapes absorption and is therefore of the bile acid pool in the enterohepatic circulation increases, eliminated in the feces. Nonetheless, this represents a major FXR is activated, and transcription of the CYP7A1 gene is sup- pathway for the elimination of cholesterol. Each day the pool pressed. Chenodeoxycholic acid is particularly important in of bile acids (about 3-5 g) is cycled through the intestine 6 to activating FXR. CYP7A1 activity is also enhanced by choles- 10 times and an amount of bile acid equivalent to that lost in terol of endogenous and dietary origin and regulated by insu- the feces is synthesized from cholesterol, so that a pool of bile lin, glucagon, glucocorticoids, and thyroid hormone.  CHAPTER 26 Cholesterol Synthesis, Transport, & Excretion 267 CLINICAL ASPECTS obesity (particularly abdominal obesity), lack of exercise, and drinking soft as opposed to hard water. Factors associ- Serum Cholesterol Is Correlated With ated with elevation of plasma-free fatty acids (FFAs) followed by increased output of triacylglycerol and cholesterol into the Incidence of Atherosclerosis & the circulation in VLDL include emotional stress and cof- Coronary Heart Disease fee drinking. Premenopausal women appear to be protected Atherosclerosis is an inflammatory disease characterized by the against many of these deleterious factors, and this is thought deposition of cholesterol and cholesteryl ester from the plasma to be related to the beneficial effects of estrogen. There is an lipoproteins into the artery wall and is a major cause of heart association between moderate alcohol consumption and a disease. Elevated plasma cholesterol levels (>5.2 mmol/L) are lower incidence of coronary heart disease. This may be due one of the most important factors in promoting atherosclero- to elevation of HDL concentrations resulting from increased sis, but it is now recognized that elevated blood triacylglycerol synthesis of apo A-I and changes in activity of cholesteryl ester is also an independent risk factor. Diseases in which there is a transfer protein. It has been claimed that red wine is particu- prolonged elevation of levels of VLDL, IDL, chylomicron rem- larly beneficial, perhaps because of its content of antioxidants. nants, or LDL in the blood (eg, diabetes mellitus, lipid nephro- Regular exercise lowers plasma LDL but raises HDL. Triacyl- sis, hypothyroidism, and other conditions of hyperlipidemia) glycerol concentrations are also reduced, due most likely to are often accompanied by premature or more severe athero- increased insulin sensitivity, which enhances the expression of sclerosis. There is also an inverse relationship between HDL lipoprotein lipase. (HDL2) concentrations and coronary heart disease, making the LDL:HDL cholesterol ratio a good predictive parameter. This When Diet Changes Fail, Hypolipidemic is consistent with the function of HDL in reverse cholesterol Drugs Can Reduce Serum Cholesterol & transport. Susceptibility to atherosclerosis varies widely among species, and humans are one of the few in which the disease can Triacylglycerol be induced by diets high in cholesterol. A family of drugs known as statins have proved highly effi- cacious in lowering plasma cholesterol and preventing heart disease. Statins act by inhibiting HMG-CoA reductase and Diet Can Play an Important Role in upregulating LDL receptor activity. Examples currently in use Reducing Serum Cholesterol include atorvastatin, simvastatin, fluvastatin, and pravas- Hereditary factors play the most important role in determining tatin. Ezetimibe reduces blood cholesterol levels by inhibiting the serum cholesterol concentrations of individuals; however, the absorption of cholesterol by the intestine via blockage of dietary and environmental factors also play a part, and the most uptake by the Niemann-Pick C-like 1 protein. Other drugs beneficial of these is the substitution in the diet of polyunsat- used include fibrates such as clofibrate, gemfibrozil, and nic- urated and monounsaturated fatty acids for saturated fatty otinic acid, which act mainly to lower plasma triacylglycerols acids. Plant oils such as corn oil and sunflower seed oil contain by decreasing the secretion of triacylglycerol and cholesterol- a high proportion of ω6 polyunsaturated fatty acids, while olive containing VLDL by the liver. Since PCSK9 reduces the num- oil contains a high concentration of monounsaturated fatty ber of LDL receptors exposed on the cell membrane, it has acids. ω3 fatty acids found in fish oils are also beneficial (see the effect of raising blood cholesterol levels, thus drugs that Chapter 21). On the other hand, butter fat, beef fat, and palm oil inhibit its activity are potentially antiatherogenic and two such contain a high proportion of saturated fatty acids. Sucrose and compounds, alirocumab and evolocumab, have recently been fructose have a greater effect in raising blood lipids, particularly approved for use and others are currently in development. triacylglycerols, than do other carbohydrates. One of the mechanisms by which unsaturated fatty acids Primary Disorders of the Plasma lower blood cholesterol levels is by the upregulation of LDL receptors on the cell surface, causing an increase in the catabolic Lipoproteins (Dyslipoproteinemias) rate of LDL, the main atherogenic lipoprotein. In addition, ω3 Are Inherited fatty acids have anti-inflammatory and triacylglycerol-lowering Inherited defects in lipoprotein metabolism lead to the pri- effects. Saturated fatty acids also cause the formation of smaller mary condition of either hypo- or hyperlipoproteinemia VLDL particles that contain relatively more cholesterol, and they (Table 26–1). For example, familial hypercholesterolemia are utilized by extrahepatic tissues at a slower rate than are larger (FH), causes severe hypercholesterolemia and is associated particles—tendencies that may be regarded as atherogenic. with premature atherosclerosis. The defect is most often in the gene for the LDL receptor, so that LDL is not cleared from the Lifestyle Affects the Serum blood. In addition, diseases such as diabetes mellitus, hypo- thyroidism, kidney disease (nephrotic syndrome), and athero- Cholesterol Level sclerosis are associated with secondary abnormal lipoprotein Additional factors considered to play a part in coronary heart patterns that are similar to one or another of the primary disease include high blood pressure, smoking, male gender, inherited conditions. Virtually all of the primary conditions 268 SECTION V Metabolism of Lipids TABLE 26–1 Primary Disorders of Plasma Lipoproteins (Dyslipoproteinemias) Name Defect Remarks Hypolipoproteinemias No chylomicrons, VLDL, or LDL are formed because Rare; blood acylglycerols low; intestine and Abetalipoproteinermia of defect in the loading of apo B with lipid. liver accumulate acylglycerols. Intestinal malabsorption. Early death avoidable by administration of large doses of fat-soluble vitamins, particularly vitamin E. Familial α-lipoprotein deficiency All have low or near absence of HDL. Tendency toward hypertriacylglycerolemia as Tangier disease a result of absence of apo C-ll, causing inactive Fish-eye disease LPL. Low LDL levels. Atherosclerosis in the Apo A-I deficiencies elderly. Hyperlipoproteinemias Hypertriacylglycerolemia due to deficiency of Slow clearance of chylomicrons and VLDL. Low Familial lipoprotein lipase deficiency LPL, abnormal LPL, or apo C-ll deficiency causing levels of LDL and HDL. No increased risk of (type I) inactive LPL. coronary disease. Familial hypercholesterolemia (type IIa) Defective LDL receptors or mutation in ligand Elevated LDL levels and hypercholesterolemia, region of apo B-100. resulting in atherosclerosis and coronary disease. Familial type III hyperlipoproteinemia Deficiency in remnant clearance by the liver is due Increase in chylomicron and VLDL remnants (broad β-disease, remnant to abnormality in apo E. Patients lack isoforms E3 of density