Chapter 5 Metabolism of Lipids

1. Chapter 5 Metabolism of Lipids Department of Biochemistry and Molecular Biology, SMC

4. Concept Lipid is a general name of fat and lipoid. they are a kind of useful organic compounds that are insoluble in water and easily soluble in organic solvents

5. Fat (Triglyceride,TG or triacylglycerole) To store and supply energy Lipid Phospholipids To be important membrane components Glycolipids Lipoid Cholesterol Cholesterol ester

6. Triglyceride (TG) or triacylglycerol (TAG) Glycerol

7. monoglyceride Phosphoglyceride glycerol TG diglyceride O ‖ —C—(CH)m—CH3 O ‖ CH3 – (CH)n –C – CH2—O O— CH CH2—O H H O ‖ —O—P—O—X ︱ OH O ‖ —C—(CH)k—CH3 H

8. Fuctions Provide energe and store energy in living body; Important component of biomembrane, especially cells; Provide essential fatty acid. Keeping body temperature stable and protect organs from damage;

9. Concept of essential fatty acid Essential fatty acid means those polyunsaturated fatty acid that we need everyday but cannot be synthesized by human body itself and must be intaked from food. include: linoleic acid, linolenic acid arachidonic acid

10. Nomenclature of polyunsaturated fatty acid ΔCoding system Linoleic acid (18:2, Δ9,12) (naming from carboxylic end) 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 CH3-CH2-CH2-CH2-CH2-CH2 CH2-CH2-CH2 CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-COOH 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 ω or n coding system (naming from methyl end) Linoleic acid (18: 2, ω- 6,9)

11. Classification of fatty acids

12. Digestion and Absorption of Lipid Small intestine Mucosa cell Bile salt lipase FFA Portal vein TG (Short&middle chain) TG glycerol emulsify blood lipase 2-monoglyceride Acyl CoA transferase TG(long chain) TG 2FFA phospholipaseA2 lysophospholipid lysophospholipid phospholipid FFA FFA CM Cholesterol esterase Lymph system FFA Cholesterol ester Cholesterol Cholesterol apolipoprotein CM (chylomicron)

13. Lysophospholipids, the products of Phospholipase A hydrolysis, are powerful detergents.

14. Section 1 Metabolism of Triglycerides

15. I. Catabolism of TG

17. Overview of triglycerides metabolism

18. Fat catabolism(lipolysis) 1.1Fat mobilization： The triacylglycerols stored in the adipocytes are hydrolyzed by lipases, to produce free fatty acids (FFA) and glycerol, which are released into the blood and utilized by other tissue cells. this process is called fat mobilization.

21. Hormone sensitive lipase (HSL) • TG lipase is the rate-limiting enzyme in the TG degradation in adipose tissue. It is also named HSL because it is regulated by some hormones. • lipolytic Hormones: adrenaline, noradrenaline, glucagons, etc. Antilipolytic Hormones: insulin

22. 1.2.1glycerol In liver, kidney, intestine

23. In muscle cells and adipocytes, the activity of glycerol kinase is low, so these tissues cannot use glycerol as fuel.

24. 1.2.2 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 three stages.

25. Stage 1 Activation of FA (cytoplasm) Irreversible reaction. Consume 2 ~P. activation of long chain fatty acids

26. Stage 2 Transport of acyl CoA into the mitochondria Carrier:carnitine ( rate-limiting step)

27. carnitine acyltransferaseⅠ

29. Stage 3: Oxidation of FA β-oxidation in one round includes: step 1:Dehydrogenation step 2:Hydration step 3:Dehydrogenation step 4:Thiolytic cleavage

30. Step 1. Dehydrogenation

31. Step 2. Hydration

32. Step 3. Dehydrogenation

33. Step 4. Thiolytic cleavage

34. β- oxidation of fatty acids

35. The β-oxidation pathway is cyclic

36. Summary fatty acyl-CoA + FAD + NAD+ + HS-CoA→fatty acyl-CoA (2 C less) + FADH2 + NADH + H+ + acetyl-CoA

37. one cycle of the β-oxidation FADH2, NADH, acetyl CoA

38. Energy yield from one molecule of palmitic acid The net ATP production: 108－2 = 106

39. 1.3 Formation and Utilization of Ketone Bodies Ketone body is a kind of intermediate products of fatty acid during its catabolism in liver, which includes acetoacetate, β-hydroxylbutyrate and acetone. Location: hepatic mitochondria Material: acetyl CoA Key enzyme: HMG-CoA synthase

42. Utilization of ketone bodies (ketolysis) at extrahepatic tissues Succinyl-CoA transsulfurase

43. HSCoA ATP AMP PPi Acetoacetate thiokinase - Lack of succinyl-CoA transsulfurase and Acetoacetate thiokinase in the liver.

44. The physiological significance of ketone body formation and utilization It is an intermediate product of fatty acid oxidation. normal level of ketone body is 0.03~0.5mmol/L. It is a pathway to output energy from liver. Important energy form that can be utilized by brain. During starving, low sugar diet or DM, ketone body formation is increased abnormally and leads to ketoacidosis.

45. 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.

47. Causes for ketoacidosis • Severe diabetes mellitus • Starvation • Hyperemesis (vomiting) in early pregnancy

48. II Anabolism of TG

49. 2.1 Synthesis site cytosol of liver, fat tissue and intestinal mucosa cells 2.2 Synthesis materials Glycerol Mainly comes from G catabolism Fatty acid Mainly comes from food fat

50. 2.3 Process: Monoglyceride (MG) pathway Site: mucosa cells of small intestine Materials: monoglyceride fatty acid absorbed from food