1. Metabolism of lipids Dr. Mamoun Ahram Biochemistry for Nursing Summer 2015

2. Sources of lipids They enter the pathways – from the digestive tract as food is broken down, – from adipose tissue, where excess lipids have been stored fatty acids released from adipose tissue associate with albumin and are transported to other tissues – from the liver, where lipids are synthesized.

3. Digestion of triglycerides

4. Why do we fell full when we eat fatty food? The presence of triacylglycerols in consumed food slows down the rate at which the mixture of partially digested foods leaves the stomach

5. Digestion of triglycerides Lipases are released from pancreas. Bile is released from gallbladder to emulsify lipids – Cholic acid is the major bile

6. Cholic acid (just like soap) Bile acids are derived from cholesterol

7. Pancreatic lipase

8. Interstitial villi

9. Lacteal (lymphatic vessel)

10. Lipid absorption Small fatty acids and glycerol are water-soluble and are absorbed directly through the surface of the villi. The water-insoluble acylglycerols and larger fatty acids are released from the micelles at the intestinal lining and absorbed.

11. Lipoproteins Because lipids are less dense than proteins, the density of lipoproteins depends on their ratio of lipids to proteins. Therefore, lipoproteins can be divided into five major types distinguishable by their composition and densities.

12. Transport of lipids back to the liver, where it is converted to bile acids. to peripheral tissues

13. Chylomicrons Chylomicrons are too large to enter the bloodstream through capillary walls. Instead, they are absorbed into the lymphatic system through lacteals within the villi and are carried to the thoracic duct where the lymphatic system empties into the bloodstream. These are the lowest-density lipoproteins because they carry the highest ratio of lipids to proteins.

14. Good versus bad cholesterol LDL (the so-called bad cholesterol) delivers more cholesterol than is needed to peripheral tissues – if not enough HDL (the so-called good cholesterol) is present to remove it, the excess cholesterol is deposited in cells and arteries. LDL also can trigger inflammation and the buildup of plaque in artery walls.

15. Lipoprotein lipase (LPL) TAGs in chylomicrons are hydrolyzed in the bloodstream by lipoprotein lipases that are anchored in capillary walls. The resulting fatty acids have two possible fates: (1)When energy is in good supply, they are converted back to TAGs for storage in adipose tissue. (2)(2) When cells need energy, the fatty acid carbon atoms are oxidized into acetyl-SCoA.

17. Fate of fatty acids Hydrolysis/ mobilization For storage In adipose tissues Lipogenesis Steroids Ketogenesis Protein metabolism

18. Lipases of adipocytes Inhibited by insulin Activated by glucagon When energy is needed, lipases within fat cells are activated by hormones (insulin and glucagon). The stored TAGs are hydrolyzed to fatty acids, and the free fatty acids and glycerol are released into the bloodstream. The fatty acids travel in association with albumins to cells where they are converted to acetyl-CoA for energy generation.

19. Glycerol Links lipid and carbohydrate metabolism The glycerol produced from TAG hydrolysis is carried in the bloodstream to the liver or kidneys, where it is converted to glyceraldehyde 3- phosphate and dihydroxyacetone phosphate (DHAP) Adipocytes do not have the kinase needed to convert glycerol to glycerol 3- phosphate, they cannot synthesize triacylglycerols

20. Leptin and grehlin Leptin, a peptide hormone, is synthesized in adipocytes and acts on the brain to stop eating it suppresses appetite. Grehlin, another peptide hormone, stimulates intense sensations of hunger.

21. Synthesis of triacylglycerols After a meal, blood glucose levels increase rapidly, insulin levels rise, and glucagon levels drop. Glucose enters cells, and the rate of glycolysis increases. Under these conditions, insulin activates the synthesis of TAGs for storage. The basic phospholipid

22. Oxidation of fatty acids The purpose is to produce coenzymes (NADH and FADH 2 ) that will enter the elelctron transport chain and produce ATP. This is done in four stages: – Activation – Transport – Beta-oxidation

23. Activation of fatty acid The fatty acid must be activated by conversion to fatty acyl-SCoA. This activation, which occurs in the cytosol. ATP is consumed.

24. Transport into mitochondrial matrix The fatty acyl-SCoA cannot cross the mitochondrial membrane by diffusion and must be transported from the cytosol into the mitochondrial matrix. Carnitine is the carrier by forming a fatty acyl-carnitine ester.

25. Beta-oxidation Step 1: Acyl-CoA dhydrogenase and its coenzyme FAD remove hydrogen atoms forming (C=C) and forming FADH 2. Step 2: The (C=C) is hydrated into (OH-) group. Step 3: the (-OH) group is oxidized into a carbonyl group (C=O) and NAD + is reduced. Step 4: the acetyl group is detached to a coenzyme A and the fatty acid is 2 carbons shorter.

26. How much energy is produced from beta-oxidation of a fatty acid? Know number of carbons of a fatty acid – Divide by two. This gives you the number of acetyl CoA produced from this fatty acid that will enter the citric acid cycle Each acetyl CoA produces 1 ATP, 3 NADH, and 1 FADH 2. – 1 NADH = 2.5 ATP molecules; 1 FADH 2 = 1.5 ATP molecules Each cycle of beta-oxidation produces 1 NADH and 1 FADH 2. This equals 4 ATP molecules. – Number of cycles = number of acetyl CoA – 1 Subtract 2 ATP molecules needed to activate the fatty acid

27. Exercises How many ATP molecules can lauric acid (a 12- carbon fatty acid)? Lauric acid is equivalent to glucose (similar molecule weight). Compare production of ATP by lauric acid to that of glucose (glucose can produce 30-35 ATP molecules). How much ATP does beta-oxidation of palmitic acid produce?

28. Ketone bodies They are produced in the liver when there is excess lipid catabolism They are hydrphilic – They can travel though the bloodstream without the need of a carrier

29. Ketogenesis (know the steps) Location: mitochondria Acetone is formed in the bloodstream by the non- enzymatic decomposition of acetoacetate and is excreted by exhalation. ketone bodies do not need protein carriers to travel in the bloodstream. Once formed, they become available to all tissues. Reversal of last step of  -oxidation

30. Use of ketone bodies (important) The skeletal muscles of a well fed and healthy person derive a small portion of their daily energy needs from acetoacetate. Heart muscles prefer ketone bodies over glucose when fatty acids are in short supply. When energy production from glucose is inadequate due to starvation, the production of ketone bodies accelerates. During the early stages of starvation, heart and muscle tissues burn larger quantities of acetoacetate, to preserve glucose for use in the brain. In prolonged starvation, the brain gets 75% of its energy needs by switching to ketone bodies.

31. Ketosis Overproduction of ketone bodies (diabetes) Ketosis results in: – Ketonuria (ketone bodies in urea)  dehydration – Ketonemia (ketone bodies in blood) – Ketoacidosis (drop in blood pH)  labored breathing

32. Ketoacidosis Because two of the ketone bodies are carboxylic acids, continued ketosis (as in untreated diabetes) leads ketoacidosis (acidosis resulting from increased concentrations of ketone bodies in the blood). The blood buffers cannot control blood pH, which drops. An individual experiences dehydration due to increased urine flow, labored breathing because acidic blood is a poor oxygen carrier, and depression. Ultimately, if untreated, the condition leads to coma and death.

33. Start of lipogenesis (biosynthesis of fatty acids) Excess of acetyl-CoA from catabolism of carbohydrates and proteins are diverted into formation of fatty acids that can then be stored. Location: cytosol Production of acetyl-CoA and malonyl-CoA, which are linked to acyl-carrier protein (ACP) in the enzyme Note: need of ATP Link to enzyme via ACP

34. Fatty acid synthase It is a multienzyme complex that contains all six of the enzymes needed for lipogenesis, with a protein called acyl carrier protein (ACP) anchored in the center of the complex. Remember: pyruvate dehydrogenase complex

35. Lipogenesis Condensation, reduction, dehydration, reduction Note; use of NADPH

36. Repeat steps In each step, malonyl- CoA is added to the reaction

37. Lipogenesis (Biosynthesis of fatty acids) OxidationSynthesis Site of reactionMitochondriaCytosol EnzymesDifferent from each other Carrier of intermediatesCoenzyme AAcyl carrier proteins ConenzymesFAD, NADNADPH Carbon removal and addition Two carbons removed at a time Two carbons added at a time

38. Can proteins be used to produce energy? Yes, but when? – When the body does not have lipids and carbohydrates to produce energy