Lipid Metabolism III Biochemistry PDF Fall 2024

Lipid Metabolism III PHM 313: Biochemistry Fall 2024 Ahmed Abu Fayyad 1 Learning Objectives Describe and apply lipids metabolism part III-Part I (cholesterol). 2 Cholesterol and Stero...

Lipid Metabolism III PHM 313: Biochemistry Fall 2024 Ahmed Abu Fayyad 1 Learning Objectives Describe and apply lipids metabolism part III-Part I (cholesterol). 2 Cholesterol and Steroid Metabolism Cholesterol, the characteristic steroid alcohol of animal tissues, performs a number of essential functions in the body. For example, cholesterol is a structural component of all cell membranes, modulating their fluidity, and, in specialized tissues, cholesterol is a precursor of bile acids, steroid hormones, and vitamin D. The liver plays a central role in the regulation of the body’s cholesterol homeostasis. For example, cholesterol enters the liver’s cholesterol pool from a number of sources including dietary cholesterol, as well as cholesterol synthesized de novo by extrahepatic tissues and by the liver itself. Cholesterol is eliminated from the liver as unmodified cholesterol in the bile, or it can be converted to bile salts that are secreted into the intestinal lumen. It can also serve as a component of plasma lipoproteins sent to the peripheral tissues. In humans, the balance between cholesterol influx and efflux is not precise, resulting in a gradual deposition of cholesterol in the tissues, particularly in the endothelial linings of blood vessels. This is a potentially life- threatening occurrence when the lipid deposition leads to plaque formation, causing the narrowing of blood vessels (atherosclerosis) and increased risk of cardio-, cerebro- and peripheral vascular disease. 3 Figure summarizes the major sources of liver cholesterol and the routes by which cholesterol leaves the liver 4 Structure of Cholesterol Cholesterol is a very hydrophobic compound. It consists of four fused hydrocarbon rings (A-D) called the “steroid nucleus”), and it has an eight- carbon, branched hydrocarbon chain attached to carbon 17 of the D ring. Ring A has a hydroxyl group at carbon 3, and ring B has a double bond between carbon 5 and carbon 6. A. Sterols Steroids with eight to ten carbon atoms in the side chain at carbon 17 and a hydroxyl group at carbon 3 are classified as sterols. Cholesterol is the major sterol in animal tissues. Note: Plant sterols, such as β-sitosterol are poorly absorbed by humans. After entering the enterocytes, they are actively transported back into the intestinal lumen. Because some cholesterol is transported as well, plant sterols appear to reduce the absorption of dietary cholesterol. This has led to clinically useful dietary treatment of hypercholesteremia. Daily ingestion of plant steroid esters (in the form of commercially available trans fatty acid–free margarine) is one of a number of dietary strategies leading to the reduction of plasma cholesterol levels. 5 B. Cholesteryl esters Most plasma cholesterol is in an esterified form (with a fatty acid attached at carbon 3), which makes the structure even more hydrophobic than free (unesterified) cholesterol. Cholesteryl esters are not found in membranes and are normally present only in low levels in most cells. Because of their hydrophobicity, cholesterol and its esters must be transported in association with protein as a component of a lipoprotein particle or be solubilized by phospholipids and bile salts in the bile. 6 Synthesis of Cholesterol Cholesterol is synthesized by virtually all tissues in humans, although liver, intestine, adrenal cortex, and reproductive tissues, including ovaries, testes, and placenta, make the largest contributions to the body’s cholesterol pool. As with fatty acids, all the carbon atoms in cholesterol are provided by acetate, and NADPH provides the reducing equivalents. The pathway is endergonic, being driven by hydrolysis of the high-energy thioester bond of acetyl coenzyme A (CoA) and the terminal phosphate bond of adenosine triphosphate (ATP). Synthesis requires enzymes in both the cytosol and the membrane of the smooth endoplasmic reticulum (ER). The pathway is responsive to changes in cholesterol concentration, and regulatory mechanisms exist to balance the rate of cholesterol synthesis within the body against the rate of cholesterol excretion. An imbalance in this regulation can lead to an elevation in circulating levels of plasma cholesterol, with the potential for vascular disease. 7 A. Synthesis of 3-hydroxy-3-methylglutaryl (HMG) CoA B. Synthesis of mevalonate 8 C. Synthesis of cholesterol 9 D. Regulation of cholesterol synthesis HMG CoA reductase, the rate-limiting enzyme, is the major control point for cholesterol biosynthesis, and is subject to different kinds of metabolic control. An increase in insulin and thyroxine favors up-regulation of the expression of the gene for HMG CoA reductase. Glucagon and the glucocorticoids have the opposite effect. 10 Inhibition by drugs: DOC The statin drugs are structural analogs of HMG CoA, and are (or are metabolized to) reversible, competitive inhibitors of HMG CoA reductase. Atorvastatin 11 Degradation of Cholesterol The ring structure of cholesterol cannot be metabolized to CO2 and H2O in humans. Rather, the intact sterol nucleus is eliminated from the body by conversion to bile acids and bile salts, which are excreted in the feces, and by secretion of cholesterol into the bile, which transports it to the intestine for elimination. 12 Called “primary” bile acids  Bile consists of a watery mixture of organic and inorganic compounds. Phosphatidylcholine (lecithin) and bile salts (conjugated bile acids) are quantitatively the most important organic components of bile. Bile can either pass directly from the liver where it is synthesized into the duodenum through the common bile duct or be stored in the gallbladder when not immediately needed for digestion. Bacteria in the intestine can remove glycine and taurine from bile salts, regenerating bile acids. They can also convert some of the primary bile acids into “secondary” bile acids by removing a hydroxyl group, producing deoxycholic acid from cholic acid and lithocholic acid from chenodeoxycholic acid 13 Enterohepatic circulation Bile salts secreted into the intestine are efficiently reabsorbed (greater than 95%) and reused. The liver converts both primary and secondary bile acids into bile salts by conjugation with glycine or taurine, and secretes them into the bile. The mixture of bile acids and bile salts is absorbed primarily in the ileum via a Na+-bile salt cotransporter. They are actively transported out of the ileal mucosal cells into the portal blood, and are efficiently taken up by the hepatocytes via an isoform of the cotransporter. Note: Bile acids are hydrophobic and require a carrier in the portal blood. Albumin carries them in a noncovalent complex, just as it transports fatty acids in blood. The continuous process of secretion of bile salts into the bile, their passage through the duodenum where some are converted to bile acids, their uptake in the ileum, and subsequent return to the liver as a mixture of bile acids and salts is termed the enterohepatic circulation. Between 15 and 30 g of bile salts are secreted from the liver into the duodenum each day, yet only about 0.5 g (less than 3%) is lost daily in the feces. Approximately 0.5 g/day is synthesized from cholesterol in the liver to replace the lost bile acids. Bile acid sequestrants, such as cholestyramine, bind bile acids in the gut, prevent their reabsorption and so promote their excretion. They are used in the treatment of hypercholesterolemia because the removal of bile acids relieves the inhibition on bile acid synthesis in the liver, thereby diverting additional cholesterol into that pathway. Note: Dietary fiber also binds bile acids and increases their excretion. 14 Enterohepatic circulation of bile salts and bile acids 15 3 Colesevelam Bile acid sequestrant 16 Plasma Lipoproteins The plasma lipoproteins are spherical macromolecular complexes of lipids and specific proteins (apolipoproteins or apoproteins). The lipoprotein particles include chylomicrons (CM), very-low-density lipoproteins (VLDL), low-density Approximate size and density of serum lipoproteins (LDL), and high-density lipoproteins (HDL). lipoproteins. Each family of lipoproteins exhibits a range of sizes They differ in lipid and protein composition, size, density, and densities; this figure shows typical and site of origin. values. The width of the rings approximates the amount of each Lipoproteins function both to keep their component component. lipids soluble as they transport them in the plasma and to [Note: Although cholesterol and its provide an efficient mechanism for transporting their lipid esters are shown as one component in contents to (and from) the tissues. the center of each particle, physically cholesterol is a surface component In humans, the transport system is less perfect than in whereas cholesteryl esters are located other animals and, as a result, humans experience a in the interior of the lipoproteins.] gradual deposition of lipid—especially cholesterol—in tissues. This is a potentially life-threatening occurrence when the lipid deposition contributes to plaque formation, causing the narrowing of blood vessels (atherosclerosis). 17 18 19 20 21 22 DOC 23  CYP inhibitors Atorvastatin, lovastatin and simvastatin are CYP3A4 substrates. In general, rosuvastatin and pravastatin have less drug interactions. 24 Cholesterol is a precursor of which of the following ? Select All That Apply A. Bile acids B. Phospholipids C. Steroid hormones D. Vitamin D E. Vitamin E 25 Cholesterol is eliminated from the liver by which of the following ways ? Select All That Apply A. As unmodified cholesterol in the bile B. It can be converted to bile salts that are secreted into the intestinal lumen C. As unmodified cholesterol in the urine D. It can serve as a component of plasma lipoproteins sent to the peripheral tissues E. It can be converted to bile salts that are secreted back into the liver 26 Which of the following represents the structure of cholesterol ? A B C D E 27 In which of the following ways cholesterol and its esters can be transported in the blood plasma ? Select All That Apply A. As a free cholesterol B. In association with protein. C. As esterified form D. As a lipoprotein E. Solubilized in the bile 28 Cholesterol is synthesized majorly by which contributors ? Select All That Apply A. Liver B. Heart C. Intestine D. Spleen E. Adrenal cortex F. Kidneys G. Ovaries H. Testes I. Placenta 29 How many steps are required to the de novo synthesis of cholesterol ? A. 3 B. 5 C. 8 D. 11 E. 12 30 Where is cholesterol synthesized ? Select All That Apply A. In the mitochondria B. Inside the cell C. In the cytosol D. Smooth ER E. Extracellular matrix 31 What type of reaction is taking place in the following ? A. Phosphorylation B. Isomerization C. Decarboxylation D. Methylation E. Transfer 32 What is the purpose of phosphorylation in the synthesis of cholesterol ? Select All Apply A. To keep water insoluble compounds in solution B. To increase solubility C. To decrease solubility D. To increase hydrophobicity E. To increase hydrophilicity 33 What is the rate-limiting enzyme in cholesterol biosynthesis A. Transferase B. HMG CoA reductase C. Kinases D. Decarboxylase E. Isomerase 34 In the case of having an increased level of cholesterol in the body, the level of HMG CoA reductase would be ? A. Increased B. Decreased C. Unchanged D. Undetermined E. Both increased and decreased. 35 Which of the following hormones favors up-regulation of the expression of the gene for HMG CoA reductase ? Select All that Apply A. Insulin B. Thyroxine C. Prolactin D. Glucagon E. Glucocorticoids 36 Cholesterol is eliminated from the body by which of the following ? Select All That Apply A. Excreted in the feces B. Reabsorbed into the liver C. Conversion to bile acids and bile salts D. Secretion into the bile E. Metabolized to CO2 and H2O 37 Complete the following, respectively. Between ______g and _____ g of bile salts are secreted from the liver into the duodenum each day, yet only about ____ g (less than 3%) is lost daily in the feces. A. 0.5, 30, & 15 B. 0.5, 15, & 30 C. 15, 30, & 0.5 D. 20, 30, & 0.5 E. 15, 20, & 0.5 38 The structural difference between cholic acid and chenodeoxycholic acid is ? A. Hydroxyl group removal at C-12 B. Hydroxyl group removal at C-7 C. Hydroxyl group removal at C-3 D. Hydroxyl group removal at C-4 E. Hydroxyl group removal at C-21 39 The lipoprotein particles in the human body include which of the following ? Select All That Apply A. TG B. Bile acids C. CM D. Bilde salts E. VLDL F. LDL G. Cholesterol H. HDL 40 A prescription for Altoprev 20 mg PO daily was brought to the pharmacy. Which of the following is the generic name for Altoprev? A. Fluvastatin B. Lovastatin C. Pravastatin D. Pitavastatin E. Rosuvastatin 41 Which of the following statins should be taken with the evening meal? A. Atorvastatin B. Lovastatin immediate-release C. Pravastatin D. Pitavastatin E. Rosuvastatin 42 Select the correct mechanism of action of cholestyramine: A. It reduces cholesterol absorption at the brush-border. B. It is a peroxisome proliferator receptor alpha activator. C. It increases HDL synthesis. D. It inhibits the enzyme HMG-CoA reductase. E. It binds to bile acids in the gut. 43 Select the correct mechanism of action of statins A. Statins inhibit the enzyme HMG-CoA reductase, blocking cholesterol synthesis. B. Statins inhibit PCSK9, resulting in increased LDL uptake into the hepatocytes. C. Statins reduce cholesterol absorption at the brush-border. D. Statins are peroxisome proliferator receptor alpha activators. E. Statins bind to and inhibit microsomal triglyceride transfer protein (MTP) in the endoplasmic reticulum. 44 Which of the following cholesterol medications should not be taken with grapefruit or grapefruit juice? A. Trilipix B. Pravachol C. Zocor D. Vascepa E. Zetia 45 A patient was prescribed Crestor 40 mg, but it is not the preferred statin on his insurance plan. Which statin would provide an equivalent dose? A. Atorvastatin 20 mg B. Pravastatin 40 mg C. Atorvastatin 40 mg D. Atorvastatin 80 mg E. Pravastatin 80 mg 46 47 1 48 2 49 3 50 4 51 5 52 6 53 7 54