Lipids and lipoproteins metabolism

2. Lipids and lipoproteins metabolism

3. Outline 1. Introduction 2. Digestion and absorption in GI 3. Formation and secretion of lipoproteins (chylomicron) by enterocytes 4. Blood circulation and targeting of dietary lipids and lipoproteins 5. Destination of fatty acids in tissues 6. Lipid transport in fed state 7. Lipid transport in fasted state 8. Oxidation of fatty acids

4. 1. Importance of lipids and lipoproteins • Heterogeneous group of water insoluble organic molecules • Major source of energy (9Kc/1gr) • Storage of energy (TAG in adipose tissue) • Amphipatic barriers (PL, FC) • Regulatory or coenzyme role (vitamins) • Control of body’s homeostasis (steroid hormones, PG) • Consequences of imbalance in lipids and lipoproteins metabolism: • Atherosclerosis • Obesity • Diabetes

5. 1. Importance of lipids and lipoproteins Atherosclerosis Obesity

6. Lipid metabolism 2. Digestion and absorption of Dietary fats in GI

7. 2.1. Dietary fats contents • Triacylglycerol (TAG) • Over 93% of the fat that is consumed in the diet is in the form of triglycerides (TG) or TAG • Cholesterol (FC, CE) • Phospholipids (PL) • Free fatty acids (FFA)

8. 2.2. Dietary sources of Lipids • Animal Sources • Vegetable Sources

9. General schematic

10. 2.3. Digestion of dietary fats • Digestion in stomach • Lingual lipase -----acid stable • Gastric lipase -----acid stable • These enzymes are most effective for short and medium chain fatty acids • Milk, egg yolk and fats containing short chain fatty acids are suitable substrates for its action • Play important role in lipid digestion in neonates

11. 2.4.Digestion in small intestine

12. 2.5. Bile Salts • Bile salts are synthesized in the liver and stored in the gallbladder • They are derivatives of cholesterol • Bile salts help in the emulsification of fats • Bile salts help in combination of lipase with two molecules of a small protein called as Colipase. This combination enhances the lipase activity

13. 2.6. Pancreatic enzymes in degradation of dietary lipids • Pancreatic Lipase (along with colipase) • Degradation of TAG • Cholesteryl estrase • Degradation of cholesteryl esters • Phospholipase A2 and lysophospholipase - Degradation of Phospholipids

14. 2.6. Pancreatic enzyme PLase A2

15. 2.7. Controlof lipid digestion • Cholecystokinin • Secretin • Bicarbonate

16. 2.8. Disorders 1. Lithiasis 2. Cystic fibrosis

17. 2.8. Disorders: Lipid Malabsorption • Steatorrhea: increased lipid and fat soluble vitamin excretion in feces. • Possible causes of steatorrehea • Colipase deficiency

18. 3. Absorption and secretion of lipids by enterocytes TAG: triacylglycerol DAG: diacylglycerol MAG: monoacylglycerol FA: fatty acid CL: cholesterol BS: bile salt LPA: lysophosphatidate CE: cholestryl ester ACAT: acyl-CoA cholesterol acyl transferase CM: chylomicron MTP: microsomal TAG transfer protein AGPAT: 1-acylglycerol-3-phosphate-O-acyltransferase

19. 3. Secretion of lipids from enterocytes • After a lipid rich meal, lymph is called chyle

20. 4. Blood circulation and targeting of dietary lipids and lipoproteins

21. 4. Blood circulation and targeting of lipids and lipoproteins

22. 4.1. ApoC-II, lipoprotein lipase (LPL) , deficiency and heparan sulfate Glycerol (exogenous) Liver Chylomicron remnant Clearing factor HDL LPL

23. 6. Destination of fatty acids in tissues • Muscle tissue and liver: Catabolism (oxidation) • The end product of FAs catabolism (acetyl-CoA): • as fuels for energy production (TCA) • as substrates for cholesterol and ketone body synthesis • Adipose tissue: Storage (TAG)

24. Glucose & other fuels Dietary TAG 7. Lipids and lipopoteins transport in fed state liver Small intestine Acetyl-CoA FAs TAG Chylomicron VLDL Chylomicron (TAGendo) and VLDL (TAGexo) Blood stream Adipose tissue FAs TAGs FAs energy Muscle

25. 8. Lipids and lipopoteins transport in long fasted state Brain liver Glucose Glycerol Ketone bodies Acetyl-CoA energy FAs Acetyl-CoA Ketone bodies FAs-albumin glycerol Blood stream ketone bodies Adipose tissue FAs+Glycerol TAGs FAs(+ketone bodies) energy Muscle

27. Pathway for catabolism of saturated fatty acids at the β carbon atom with successive removal of two carbon atoms as acetyl CoA • Site: • Cytosol (activation) • Mitochondria • Membrane transport • Matrix ( β oxidation)

28. 9.1.1. Activation and transport of fatty acids into mitochondria Acyl CoA synthase

29. 9.1.1. Entry of short and medium chain FA into mitochondria • Carnitine and CAT system not required for fatty acids shorter than 12 carbon length. • They are activated to their CoA form inside mitochondrial matrix.

30. 9.1.1.1. Carnitine deficiencies • Primary causes: • Carnitineacyltransferase-I (CAT-I) deficiency: mainly affects liver • Carnitineacyltransferase-II (CAT-II) deficiency: mainly affects skeletal and cardiac muscles. • Secondary causes : • liver diseases: decreased endogenous synthesis

31. 9.1.1.1. Consequence of carnitine deficiencies • Excessive lipid accumulation occurs in muscle, heart, and liver • Cardiac and skeletal myopathy • Hepatomegaly • Low blood glucose in fasted state hypoglycemia coma

33. Provision of energy • Major pathway of acetyl-CoA • Cholesterol production • Ketone bodies production • Diabetes • Starvation

34. Types of fatty acyl CoA dehydrogenases • Long chain fatty acyl CoA dehydrogenase (LCAD) • Medium chain fatty acyl CoA dehydrogenase (MCAD) • Short chain fatty acyl CoA dehydrogenase (SCAD) MCAD deficiency is thought to be one of the most common inborn errors of metabolism.

35. The first level Muscle tissue and liver The second level TAG FFA Glucagon Epinephrine Insulin The third level FFA + - CAT1 Acetyl-CoA FFA - TCA NADH Adipose tissue Malonyl-CoA Acetyl-CoA and NADH inhibition of ᵦ oxidation enzymes

36. Peroxisomal FA oxidation • Acts on very long chain fatty acids (VLCFAs) • Zellweger syndrome • Absence of peroxisomes • Rare inherited disorder • VLCFA cannot be oxidized • Accumulation of VLCFA in brain, blood and other tissues like liver and kidney

37. Omega oxidation • It is a minor pathway • Takes place in microsomes • Involves oxidation of last carbon atom ( ω carbon) • More common with medium chain fatty acids

38. Alpha oxidation • Seen in branched chain fatty acid, phytanic acid • Occurs in endoplasmic reticulum • Refsum disease • Genetic disorder • Caused by a deficiency of alpha hydroxylase • There is accumulation of phytanic acid in the plasma and tissues. • The symptoms are mainly neurological.

39. GLC Protein Ketone bodies HMG-CoA FA TAG & PL Acetyl-CoA HMG-CoA Cholesterol TAG- Protein -Glucose Acetyl CoA and lipid metabolism Mitochondria Cytosol TCA Pentose phosphate pathway

40. De Novo synthesis of fatty acids • Saturated fatty acids are synthesized from acetyl CoA • Occurs in cytoplasm • Occurs mainly in liver, adipose tissue and lactating mammary gland • Need to • acetyl CoA • NADPH

41. De Novo synthesis of fatty acids • Phase I • Transport of substrates into cytosol • Carboxylation of acetyl-CoA to malonyl-CoA • Phase II • Utilization of substrate to form palmitate by fatty acid synthase complex • Phase III • Elongation and desaturation of palmitate to generate different fatty acids

42. Acetyl CoA activation and regulation of it + Glucagon and epinephrine

43. Synthesis of palmitate by fatty acid synthase(FAS)

44. Modification of dietary and endogenous fatty acids • Chain elongation to give longer fatty acids • Desaturation, giving unsaturated fatty acids

45. ω-3 ω-6 ω-7 ω-9 Modification of dietary and endogenous fatty acids Essential fatty acids

46. TAG formation Glycerol Glucose Pyruvate Dihydroxy acetone phosphate Glycerol 3-P 1acyl-dihydroxy acetone phosphate 1acyl- glycerol 3-P 1,2Diacyl- glycerol 3-P (phosphatidate) Diacylglycerol Monoacylglycerol TAG ATP ADP NADH, H+ NAD+ Acyl-CoA Acyl-CoA CoA NADH, H+ CoA NAD+ Acyl-CoA CoA Pi Acyl-CoA CoA Acyl-CoA CoA

47. Fates of TAG in liver and adipose tissue • Adipose tissue: TAG stored in cytosol • Liver: very little stored. Exported out of liver in VLDL , which exports endogenous lipids to peripheral tissues

48. Lipogenesis Lipolysis FFA Lipolysis

49. + HSL-P Mobilization of stored fats and release of FAs Glucagon & epinephrine P P P P P P HSL

50. Metabolism of cholesterol