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Introduction to Lipid/Fat Metabolism

This chapter provides an introduction to lipid metabolism, focusing on the roles of fatty acids in the cell, the oxidation of fatty acids for energy production, the catabolism of odd-carbon fatty acids, the metabolism of unsaturated fatty acids, the production of ketone bodies, and fatty acid synthesis.

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Introduction to Lipid/Fat Metabolism

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  1. Lipid/Fat metabolism Chapter 4

  2. Introduction • Fatty acids have 4 major roles in the cell: • Building blocksof phospholipids and glycolipids • Added onto proteins to create lipoproteins, which targets them to membrane locations • Fuel molecules - source of ATP • Fatty acid derivatives serve as hormones and intracellular messengers

  3. The oxidation of f.acids – source of energy in the catabolism of lipids • Both triacylglycerols and phosphoacylglycerols have f.acids as part of their covalently bonded structures • The bond between the f.acids and the rest of the molecule can be hydrolyzed (as shown in the fig.) Fig. 21-1, p.569

  4. Fig. 21-2, p.569

  5. p.569

  6. Fig. 21-3, p.570

  7. Fatty acids oxidation begins with activation of the molecule. • A thioester bond is formed between carboxyl group of f.acid and the thiol group of coenzyme A (CoA-SH) (esterification reaction – in cytosol)

  8. Fig. 21-5, p.571

  9. Fig. 21-6, p.572

  10. When a f.acid with an even number of C atoms undergoes successive rounds of β-oxidation cycle, the product is acetyl-CoA. • No. of molecules of acetyl-CoA produced = ½ the no. of C atoms in the original f.acid. (as shown in fig above) • The acetyl-CoA enters the TCA cycle (the rest of oxidation to CO2 and H2O taking place via TCA cycle and ETC) • β-oxidation takes place in mitochondria.

  11. The energy released by the oxidation of acetyl-CoA formed by β-oxidation of f.acids can be used to produce ATP. • There are two sources of ATP: • Reoxidation of the NADH and FADH2 produced by β-oxidation • ATP production from processing acetyl-CoAvia TCA cycle and oxidative phosphorylation • NADH and FADH2produced by β-oxidation and TCA cycle enter ETC and ATP produced through oxidative phosphorylation Table 21-1, p.575

  12. Comparison Carbohydrate Lipids • 32 moles of ATP produced from complete oxidation of CHO (but, glucose is 6C atoms, so 6 x 3 = 18 C atoms. Therefore, 32 x 3 = 96 ATP. • e.gstearic acid: 18 C atoms = produced 120 moles of ATP • Reason? • F.acid is all hydrocarbon except carboxyl group – exists in highly reduced state • H2O is produced in oxidation of f.acids – can be a source of water for organisms that live in desert

  13. Camel Kangaroo rats p.575a

  14. The catabolism of odd-carbon f.acids Fig. 21-8, p.576

  15. The catabolism of unsaturated f.acids • The -oxidation of unsaturated f.acids • does not generate as many ATPs as it would for a saturated f.acids (same C atoms) – the presence of double bond • the acyl-deH2ase step skipped – fewer FADH2 will be produced

  16. Fig. 21-9b, p.577

  17. Fig. 21-10a, p.578

  18. Fig. 21-10b, p.578

  19. Ketone bodies • Substances related to acetone (“ketone bodies”) are produced when an excess of acetyl-CoA arises from β-oxidation • Occurs because when there are not enough OAA to react with acetyl-CoA in TCA cycle • When organisms has a high intake of lipids and low intake of CHO or starvation and diabetes • The reactions that result in ketone bodies start with the condensation of two molecules of acetyl-CoA to produce acetoacetyl-CoA

  20. the odor of acetone can be detected on the breath of diabetics whose not controlled by suitable treatment • Acetoacetate and β-hydroxybutyrate are acidic, their presence at high [ ] overwhelms the buffering capacity of the blood • to lowered the blood pH is dealt by excreting H+ into the urine, accompanied by excretion of Na +, K + and water → results in severe dehydration and diabetic coma • synthesis of ketone bodies in liver mitochondria • transport ketone bodies in the bloodstream; water soluble • other organs such as heart muscle and renal cortex can use ketone bodies (acetoacetate) as the preferred source of energy • even in brain, starvation conditions lead to the use of acetoacetate for energy

  21. FATTY ACID SYNTHESIS • The anabolic reaction takes place in cytosol • Important features of pathway: • Intermediates are bound to sulfhydral groups of acyl carrier protein (ACP); intermediates of β-oxidation are bonded to CoA • Growing fatty acid chain is elongated by sequential addition of two-carbon units derived from acetyl CoA • Reducing power comes from NADPH; oxidants in β-oxidation are NAD+ and FAD • Elongation of fatty acid stops when palmitate (C16) is formed; further elongation and insertion of double bonds carried out later by other enzymes

  22. Step 1 Fig. 21-12, p.581

  23. Step 2 Fig. 21-13, p.581

  24. Malonyl-CoA inhibits carnitine acyltransferase I Fig. 21-14b, p.582

  25. Pathway of palmitate synthesis from acetyl-CoA and malonyl-CoA The biosynthesis of f.acids involves the successive addition of two-carbon units to the growing chain. - Two of the three C atoms of the malonyl group of malonyl-CoA are added to the growing fatty-acid chain with each cycle of the biosynthetic reaction Fig. 21-15, p.583

  26. Fig. 21-15a, p.583

  27. Step 3 Fig. 21-15b, p.583

  28. This reaction require multienzyme complex : fatty acid synthase Step 4 Fig. 21-15c, p.583

  29. Fig. 21-16, p.584

  30. There are several additional reactions required for the elongation of f.acid chain and the introduction of double bonds. When mammals produce f.acids with longer chains than that of palmitate, the reaction does not involve cytosolic f-acid synthase. There are two sites for chain lengthening reactions: ER (endoplasmic reticulum) and mitochondrion. Table 21-2, p.586

  31. Fig. 21-17, p.586

  32. Table 21-3, p.599

  33. Lipids are transported throughout the body as lipoproteins • Both transported in form of lipoprotein particles, which solubilize hydrophobic lipids and contain cell-targeting signals. • Lipoproteins classified according to their densities: • chylomicrons - contain dietary triacylglycerols • chylomicron remnants - contain dietary cholesterol esters • very low density lipoproteins (VLDLs) - transport endogenous triacylglycerols, which are hydrolyzed by lipoprotein lipase at capillary surface • intermediate-density lipoproteins (IDL) - contain endogenous cholesterol esters, which are taken up by liver cells via receptor-mediated endocytosis and converted to LDLs • low-density lipoproteins (LDL) - contain endogenous cholesterol esters, which are taken up by liver cells via receptor-mediated endocytosis; major carrier of cholesterol in blood; regulates de novo cholesterol synthesis at level of target cell • high-density lipoproteins - contain endogenous cholesterol esters released from dying cells and membranes undergoing turnover

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