Ch. 25: Lipids Metabolism

1. Ch. 25: Lipids Metabolism

2. Digestion of Triacylglycerols • Lipids in our diet make us feel full after eating; lipids in food slow digestion. • Lipids are packaged as lipoproteins for transport. • Arrival of chyme in the small intestine triggers release of pancreatic lipases and bile. • -Bile contains bile acids and salts that emulsify lipids for digestion. Cholic acid is the major bile acid. These molecules use their hydrophilic and hydrophobic regions to emulsify the lipid droplets so they can be acted on by the pancreatic lipases

4. Larger fatty acids form micelles with the help of phospholipids and bile acids. • Other, insoluble lipids are emulsified by bile acids and carried to the intestinal lining. • Here they are assembled into triacylglycerols and packaged into chylomicrons, which enter the lymphatic system for transport to the thoracic duct.

5. Pancreatic lipase hydrolyzes some of the lipids, forming mono- and diacylglycerols, fatty acids, and a little glycerol. • Glycerol and small fatty acids are water-soluble and pass through villi into the bloodstream.

6. Lipoproteins for Lipid Transport • Triacylglycerols and fatty acids must be solubilized for transport by association with water-soluble proteins. • Fatty acids usually associate with albumin for transport. • Chylomicrons are lipid-protein complexes which transport triacylglycerols (TAGs) through the lymphatics. • Chylomicrons have a very high ratio of lipid to protein.

7. Lipoproteins for Lipid Transport Cont. • Very-low density lipoproteins (VLDLs) carry triacylglycerols from liver to peripheral tissues for storage or catabolism. • Lipoproteins usually have a core of lipid surrounded by a layer of phospholipids and proteins that are soluble in blood plasma. • Low-density lipoproteins (LDLs) carry cholesterol from liver to peripheral tissues. • IDLs (Intermediate-density lipoproteins) carry remnants of VLDLs back to liver for synthesis. • High-density lipoproteins (HDLs) carry cholesterol (often from dead or dying cells) to liver for conversion to bile acids, which are used in digestion or excreted.

8. A lipoprotein contains a core of neutral lipids, including triacylglycerols and cholesteryl esters. Surrounding the core is a layer of phospholipids in which varying proportions of proteins and cholesterol are embedded. A lipoprotein is a lipid-protein complex that transports lipids.

9. Fatty acids released from storage are carried by albumin, which is a large protein. All of the other lipids are carried packaged in various lipoproteins. Transport of lipids.

10. left to right, the lipoproteins shown are chylomicrons (magnified 43,000x), VLDLs(130,000x), LDLs(130,000x), and HDLs (130,000x). These lipoproteins were separated from blood plasma in an ultracentrifuge and photographed with an electron microscope. From left to right, the lipoproteins shown are chylomicrons Lipoproteins

11. Pathways that break down molecules (catabolism) are shown in yellow, and synthetic pathways (anabolism) are shown in blue. Connections to other pathways or intermediates of metabolism are shown in green. Metabolism of triacylglycerols

12. Acetyl-SCoA participates in • Triacylglycerol synthesis • Ketone body synthesis • Synthesis of steroids and other lipids • Citric acid cycle and oxidative phosphorylation

13. Triacylglycerol Metabolism: • The passage of fatty acids in and out of storage in adipose tissue is a continuous process essential to maintaining homeostasis. • After a meal, blood glucose levels are high and insulin activates the synthesis of TAGs for storage. • The metabolism of glucose is needed to supply dihydroxyacetone phosphate that isomerizes to give the necessary glycerol 3-phosphate because adipocytes do not have the enzyme needed to convert glycerol to glycerol 3-phosphate

14. The reactants in TAG synthesis are glycerol 3-phosphate and fatty acid acyl groups carried by coenzyme A. • TAG synthesis proceeds by transfer of first one and then another fatty acid acyl group from coenzyme A to glycerol 3-phosphate.

15. Next, the phosphate group is removed and the third fatty acid group is added to give a triacylglycerol. • When digestion of a meal is finished, blood glucose levels are low; consequently insulin levels drop and glucagon levels rise.

16. The lower insulin level and higher glucagon level together activate triacylglycerol lipase, the enzyme within adipocytes that controls hydrolysis of stored TAGs. • When glycerol 3-phosphate is in short supply, an indication that glycolysis is not producing sufficient energy, the fatty acids and glycerol produced by hydrolysis of the stored TAGs are released to the bloodstream for transport to energy-generating cells. • Mobilization (of triacylglycerols): Hydrolysis of triacylglycerols in adipose tissue and release of fatty acids into the bloodstream.

17. Oxidation of Fatty Acids: three-step process • The fatty acid is activated by the conversion to fatty acyl-SCoA, a form that breaks down more easily. • Transportinto the mitochondrial matrix where energy generation will occur. Carnitine, a transmembrane protein found only in the mitochondrial membrane, specifically moves fatty acyl-SCoA across the membrane into the mitochondria. • The oxidation occurs by repeating the series of four reactions which make up the b-oxidation pathway. The fatty acyl-SCoA must be oxidized by enzymes in the mitochondrial matrix to produce acetyl-SCoA plus the reduced coenzymes to be used in ATP generation.

18. b-Oxidation refers to the oxidation of the carbon atom b to the thioester linkage in two steps of the pathway. • The first b-oxidation: The oxidizing agent FAD removes hydrogen atoms from the carbon atoms a and b to the C=O group in the fatty acyl-SCoA, forming a carbon–carbon double bond.

19. Hydration: A water molecule adds across the newly created double bond to give an alcohol with the –OH group on the b-carbon. • The second b-oxidation: NAD+is the oxidizing agent for conversion of the b-OH group to a carbonyl group. • Cleavage to remove an acetyl group: An acetyl group is split off and attached to a new coenzyme A molecule, leaving behind an acyl-SCoA that is two carbon atoms shorter.

20. The beta β oxidation of fatty acids. Passage of an acyl-SCoA through these four steps cleaves one acetyl group from the end of the fatty acid chain. In this manner, carbon atoms are removed from a fatty acid two at a time

21. Energy from Fatty Acid Oxidation • In effect, 2 ATP were used to form a fatty acyl-SCoA. • In fatty acid oxidation, each acetyl-SCoA can pass carbons into the citric acid cycle, yielding 12 ATP. • Each of the FADH2 molecules can be oxidized via the electron transport chain to form a maximum of 2 ATP, and each NADH can result in formation of 3 ATP. • One mole of lauric acid weighs about the same as one mole of glucose.

22. 12 carbons as lauric acid can form 6 acetyl-SCoA's, each worth 12 ATP. • 6 acetyl-SCoA yield 12 ATP/acetyl-SCoA 72 ATP • β-oxidations occur, each yielding an FADH2 and a NADH. • 5 FADH2 each yielding 2 ATP 10 ATP • 5 NADH each yielding 3 ATP15 ATP • 2 ATP were used to start: ATP–> AMP + pyrophosphate–2 ATP • Net energy production from 12 carbons as lauric acid:95 ATP • One mole of glucose (180 grams) yields 38 ATP. Obviously, a much higher energy yield is obtained by oxidation of fatty acids than glucose. Six carbons as glucose would yield 2 (38) ATP, or 76 ATP. • In addition, glycogen is much more highly hydrated, so a typical person would need to weigh about 120 pounds more to carry his or her reserve energy supply as starch.

23. Ketone Bodies and Ketoacidosis • Ketone bodies: Compounds produced in the liver that can be used as fuel by muscle and brain tissue: • 3-hydroxybutyrate • acetoacetate • acetone. • Ketogenesis: The synthesis of ketone bodies from acetyl-SCoA. • In starvation or diabetes, lipid breakdown produces more acetyl-SCoA than can be oxidized by the citric acid cycle. Under these conditions, the excess acetyl-SCoA may form ketone bodies such as acetone, acetoacetic acid, or 3-hydroxybutyate.

24. Under well-fed, healthy conditions, skeletal muscles derive a small portion of their daily energy needs from acetoacetate, and heart muscles use it in preference to glucose. • During the early stages of starvation, heart and muscle tissues burn larger quantities of acetoacetate, thereby preserving glucose for use in the brain. In prolonged starvation, even the brain can switch to ketone bodies to meet up to 75% of its energy needs. • The condition in which ketone bodies are produced faster than they are utilized (ketosis) occurs in diabetes. It is indicated by the odor of acetone (a highly volatile ketone) on the patient’s breath and the presence of ketone bodies in the urine (ketonuria) and the blood (ketonemia).

25. Two of the ketone bodies are carboxylic acids. Ketoacidosis results from increased concentrations of ketone bodies in the blood. The blood’s buffers are overwhelmed and blood pH drops. Ketoacidosis causes dehydration due to increased urine flow, labored breathing because acidic blood is a poor oxygen carrier, depression, and ultimately, if untreated, the condition leads to coma and death.

26. Biosynthesis of Fatty Acids • The first step of fatty acid biosynthesis or lipogenesis is transfer of an acetyl group from acetyl-SCoA to acyl carrier protein (ACP) forming acetyl-SACP and the addition of carbon dioxide (as bicarbonate) to another molecule of acetyl-SCoA, converting it to malonyl-SCoA. (This requires energy from ATP.) The malonyl group is transferred to ACP, forming malonyl-SACP. • The acyl group from acetyl-SACP is transferred to malonyl-SACP and CO2 is lost, forming a molecule of acetoacetyl-SACP (3-ketoacyl-SACP).

27. Biosynthesis cont. • From here on, the process occurs nearly as a reverse of β-oxidation. • The 3-ketoacyl-SACP is reduced to 3-hydroxyacyl-SACP. NADPH is the source of electrons and hydrogens. • Water is lost, forming a double bond. • The double bond is reduced to an alkane-type chain. NADPH is the source of the hydrogens. • More cycles can occur to lengthen the chain