Chapter 5 Lipid Metabolism 脂 (zhī) 类 (lèi) 代 (dài) 谢 (xiè)

1. Chapter 5 Lipid Metabolism脂(zhī)类(lèi)代(dài)谢(xiè)

2. Contents Section 1 Overview Section 2 Triglycerid Metabolism Section 3 Phospholipid Metabolism Section 4 Cholesterol Metabolism Section 5 Lipid Transport in Plasma

3. Section 1 Overview 概(gài)述(shù)

4. § 1.1 Lipids are water-insoluble organic compounds essential for living organisms Concept • Lipids are substances that are insoluble or immiscible in water, but soluble in organic solvents.

5. 脂(zhī)肪(fáng) Fats (Triglyceride or triacylglycerole) To store and supply energy Lipids Phospholipids To be important membrane components Glycolipids Lipoids Cholesterol 类(lèi)脂(zhī) Cholesterol ester Variable fat Basic fat

6. Classification of fatty acids

7. Essential Fatty Acids (EFA) • Linoleic,linolenic and arachidonic acids are called essential fatty acids. All of them are polyunsaturated fatty acids. Concept • Essential fatty acids (必(bì)需(xū)脂(zhī)肪(fáng)酸(suān) ), or EFAs, are fatty acids that humans and other animals must ingest (be obtained through diet) because the body requires them for good health but cannot synthesize them.

8. § 1.2 Digestion of dietary lipids requires bile salts and pancreatic enzymes • Please study by yourself. § 1.3 Digested products of lipids are assembled in intestinal mucosa cells

9. Glycocholate(甘(gān)氨(ān)胆(dǎn)酸(suān)): The main bile salts with a hydrophilic and a hydrophobic surfaces could emulsify macroscopic fat into microscopic micelles.

11. Section 2 Triglyceride Metabolism甘(gān)油(yóu)三(sān)酯(zhǐ)的(de)代(dài)谢(xiè)

12. Triglyceride (TG) or triacylglycerol (TAG)

13. Chemical Structure of Triglyceride

14. Overview of triglycerides metabolism

15. § 2.1 Degradation of Triglyceride § 2.1.1 Mobilization of stored triglycerides in adipose tissue is catalyzed by hormone sensitive lipase (lipolysis) § 2.1.2 Fatty acids are oxidized to acetyl-CoA, NADH and FADH2 byβ-oxidation of fatty acids § 2.1.3 The liver converts excess fatty acids to ketone bodies § 2.1.4 Glycerol may enter cellular glycolysis or gluconeogenesis for metabolism

16. § 2.1.1 Mobilization of stored triglycerides in adipose tissue is catalyzed by hormone sensitive lipase Concept • Fat mobilization(脂(zhī)肪(fáng)动(dòng)员(yuán))is a process that the triglyceride stored in the adipocytes are hydrolyzed by lipases to produce free fatty acids (FFA) and glycerol, which are released into blood and supplied to oxidative utilization.

18. Hormone sensitive lipase (HSL)激(jī)素(sù)敏(mǐn)感(gǎn)脂(zhī)肪(fáng)酶(méi) • Triglyceridelipase in adipose tissue is a key enzyme for fat mobilization. It is also named hormone sensitive lipase (HSL) because its activity is regulated by some hormones.

19. Effect of hormones on lipolysis via HSL • Lipolytic Hormones: • Epinephrine • 肾(shèn)上(shàng)腺(xiàn)素(sù) • Norepinephrine • 去(qù)甲(jiǎ)肾(shèn)上(shàng)腺(xiàn)素(sù) • Adrenocorticotropic hormone (ACTH) • 促(cù)肾(shèn)上(shàng)腺(xiàn)皮(pí)质(zhì)激(jī)素(sù) • Thyroid stimulating hormone (TSH) • 促(cù)甲(jiǎ)状(zhuàng)腺(xiàn)激(jī)素(sù) • Glucagon • 胰(yí)高(gāo)血(xuè)糖(táng)素(sù) • Antilipolytic Hormones: • Insulin • 胰(yí)岛(dǎo)素(sù)

20. The free fatty acids are thus released diffusively from the adipocyte into the blood, where they bind to the serum albumin (白(bái)蛋(dàn)白(bái))and transfer to other organs. • Glycerol (甘(gān)油(yóu)) can be transport to liver freely because it is soluble in water.

21. Summary

22. § 2.1.2 Fatty acids are oxidized to acetyl-CoA, NADH and FADH2 byβ-oxidation of fatty acids • Fatty acids are one of the main energy materials of human and other mammalian. • Fatty acid catabolism can be subdivided into 4 stages.

23. Stage 1 Activation of Fatty Acids • Acyl-CoA Synthetase (fatty acid thiokinase) catalyzes the activation of long chain fatty acids, which locates in cytoplasm, such as on the outer mitochondrial membrane and endoplasmic reticulum membrane.

24. Key points of FA activation • Irreversible • Consume 2 ~P (2 ATP) • Site: outside mitochondria

25. Stage 2Transport of Acyl CoA into Mitochondria ( rate-limiting step) • Carrier:carnitine

26. (-) Malonyl-CoA Rate-limiting (key) enzyme • carnitine acyltransferase Ⅰ

27. Carnitine:acyl-carnitine transferase

28. Stage 3: β-Oxidation of Fatty Acids β-oxidation means β-C reaction. Four steps in one cycle step 1:Dehydrogenation step 2:Hydration step 3: Re-dehydrogenation step 4:Thiolysis

29. 1.5 ATP Step 1. Dehydrogenation

30. Step 2. Hydration

31. 2.5 ATP Step 3. Re-dehydrogenation

32. Step 4. Thiolytic cleavage

33. 1.5 ATP 2.5 ATP Summary of fatty acid β- oxidation

34. The β-oxidation pathway is cyclic

35. Summary • One cycle of the β-oxidation of fatty acids: fatty acyl-CoA + FAD + NAD+ + HS-CoA→ fatty acyl-CoA (2 C less) + FADH2 + NADH + H+ + acetyl-CoA • The products of β-oxidation are in the forms of FADH2, NADH and acetyl CoA.

36. Stage 4 Oxidation of Acetyl CoA • All of acetyl CoA can be oxidized through Krebs cycle. And then ATP can be produced by oxidative phosphorylation.

37. Energy yield from one molecule of palmitic acid The net ATP production for one molecule of palmitic acid: 80+10.5+17.5-2 = 106

38. A simple formula of calculating ATP net products for any long chain saturated fatty acid with even carbon atoms:

39. Question: • After one molecule of stearic acid (18C) is oxidized completely, how many could the net ATP be produced? And how about myristic acid (14C)?

40. § 2.1.3 The liver converts excess fatty acids to ketone bodies Concept • Ketone bodies (酮(tóng)体(tǐ)) are a group of metabolic intermediates, which can be produced in liver through fatty acid degradation, including acetoacetate, β-hydroxybutyrate and acetone.

41. Chemical Structures of Ketone Bodies

42. The formation of ketone bodies (Ketogenesis) Location: hepatic mitochondria Material: acetyl CoA Rate-limiting enzyme: HMG-CoA synthase

44. 2.5 ATP 10 ATP • Utilization of ketone bodies (ketolysis) in extrahepatic tissues, including brain, heart, muscle and kidney.

45. - 2 ATP • Because the deficiency of succinyl-CoA transsulfurase and acetoacetate thiokinase, ketone bodies could not be oxidized for their utilization in liver.

46. Questions: • After one molecule of β-hydroxybutyrate is oxidized completely by succinyl CoA transsulfurase pathway, how many could the net ATP be produced? And how about acetoacetate? • After one molecule of β-hydroxybutyrate is oxidized completely by acetoacetate thiokinase pathway, how many could the net ATP be produced? And how about acetoacetate?

47. Physiological Significances • Ketone bodies are water-soluble fuels normally exported by the liver. • Normal physiological responses to carbohydrate shortages cause the liver to increase the production of ketone bodies from the acetyl-CoA generated from fatty acid oxidation.

49. Plasma concentrations of metabolic fuels (mmol/L) in the fed and starving states

50. Ketone bodies could replace glucose as the major source of energy for many tissues especially the brain, heart and muscles during times of prolonged starvation and severe diabetes mellitus.