1. Lipids Dr. Sooad Al-Daihan Biochemistry department

2. Lipids Heterogeneous group of biomolecules. Water insoluble (hydrophobic). Soluble in organic and non- polar solvents acetone, ether, chloroform and benzene.

3. Classes of lipids Conjugated (complex) lipids Derived lipids - Triglycerides - Waxes -Phospholipids, - Glycolipids - Sphingo- phospholipids - Lipoproteins. -Fatty acids -Cholesterol -Ketone bodies Esters of FA with alcohols Esters of FA with alcohols and additional group Obtained on hydrolysis of simple or complex lipids Simple lipids

4. source of energy Major source of energy for the body: Fat stored in the adipose tissue is a direct and potential source of energy. 1 gm lipids  9.3 Kcal 1 gm CHO  4.1 Kcal triglyceride Storage form of energy-triglyceride structural components Serve as structural components of cell membrane (PLs, glycolipids). hormones Some are hormones e.g. steroid hormone (cortisol, aldosterone, sex hormones). Essential in the diet Essential in the diet to provide the body with some essential FA and of fat- soluble vitamins (A, D, E,K) which have regulatory or coenzyme function Functions

5. 100-150 g An adult man eats about 100-150 g of lipids/day The main lipids in diet are TG which constitute most of fat and oils we eat, but diet contains also some cholesterol and phospholipids Digestion and Absorption of Lipids

6. STEP 3 Liver releases bile acids to solubilize lipid products in mixed micelles STEP 2 Pancreas releases: Lipase (+colipase) cholesterol esterase phospholipase A 2 Lipids: Triacylglycerols Cholesterol esters Phospholipids pancreas liver STEP 4 Lipids absorbed from micelles into epithelial cells STEP 5 Chylomicrons form and travel through lymphatics Gastric Lipase STEP 1 small intestine stomach pH opt ~5, Initiates hydrolysis and acts on TG with short chain FAs Lingual lipase begins emulsification of lipids and PLs (negligible)

7. Lipid emulsification  Bile acids help emulsifying fat droplets thus increasing their surface area

8. Pancreatic lipase Pancreatic lipase, also known as pancreatic triacylglycerol lipase, is secreted from the pancreas, and is the primary lipase (enzyme) that hydrolyze dietary fat molecules in the human digestive system. converting TG to monoacylglycerol and free fatty acid. Triacylglycerol + 2 H 2 O 2-monoacylglycerol + 2 fatty acid Unlike some pancreatic enzymes that are activated by proteolytic cleavage (e.g. trypsinogen), pancreatic lipase is secreted in its final form. colipase However it only becomes efficient in the presence of colipase in the duodenum.

9. Glycerol + two fatty acids + phosphorus Phosphorus part makes it soluble in water Fatty acids make it soluble in fat Therefore can serve as an emulsifier Key role is in cell membranes CH2 – O – C - R1 CH2 – O – P – O - X R2 - C - O - CH O-O- O O O O Phospholipid Is secreted by the pancreas into the intestine where it is activated by trypsin and its activity requires the presence of bile salts and calcium ions. Phospholipase A 2

10. A phospholipase is an enzyme that hydrolyzes Phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D, distinguished by the type of reaction which they catalyze: I. Phospholipase A Phospholipase A1-cleaves the SN-1 acylchain. Phospholipase A2- cleaves the SN-2 acylchain. II. Phospholipase B - cleaves both SN-1 and SN-2 acylchain. III. Phospholipase C - cleaves before the phosphate, and a phosphate- releasing diacylglycerol containing head group. IV. Phospholipase D - cleaves after the phosphate.Continue

11. The end product of lipid digestion are: MG FA (short FA C4-C10; long chain FA C12-C18) Glycerol LysoPL Cholesterol Absorption of Lipids

12. Absorption of lipids MG FA LysoPL Cholesterol + Bile Salts Micelles Bile Salts Cholesterol LysoPL Chylomicrons MG Long chain FA TGTG Glycerol Short chain FA Glycerol Short chain FA Protein LUMEN INTESTINAL WALL Systematic Circulation Thoracic Duct (No need for bile acids) PL

13. Absorption of lipids Short chain fatty acids and glycerol are water soluble and pass via the portal system directly to the liver Other lipid are water insoluble. They combine with bile salts to form a water soluble complex called micelles which enter the mucosal cells (move down concentration gradient passive diffusion) Bile salts are reabsorbed to the liver again

14. Long chain fatty acid are activated in the mucosal cells and combine with monoglycerols again to reform triglycerides The TG, PL, and cholesterol combine with protein forming chylomicrons which enter the circulation via lacteals and thoracic duct Body tissues can extract whatever fat they need from chylomicrons After absorption, lipids are either oxidized mainly in the liver or are stored in the depot (adipose tissue)

15. Fate of Dietary Lipids TG in chylomicron are degraded to glycerol + FFA by Lipoprotein lipase in the luminal surface of capillary bed. Lipoprotein Lipase FFA + Glycerol Taken up by liver Taken up by peripheral tissues (muscles, adipocytes) May bind to albumin and transported to other cells Chylomicron remnants Taken up by liver TG Chylomicron

16. 1. Tissue lipids Included in the structure of the cell e.g. Cell membrane and mitochondria. Never be oxidized to give energy. Appears as a yellow droplets in the cytoplasm of adipose tissue cells  Body lipids are 2 types: Tissue lipids depot fat (adipose tissue)

17. Continue… Sites: Under skin and breast. Around important organs e.g. kidneys. In the omentum and mesentery.Composition: Mainly TG which contains saturated and unsaturated. Fas Contains also a little of PLs and cholesterol Sources: Absorbed Fat Carbohydrates by lipogenesis

18.  Functions: Important source of energy Supports some of the internal organs like the kidney. 7-dehydrocholesterol present in adipose tissue gives Vit D 3 on exposure to UV rays. Protection of bony prominence. Protection against cold, Continue…

19. In animal that are in caloric balance, the stored TG in adipose tissue is continuously undergoing lipolysis and reesterification Metabolism of adipose tissue FA Glycerol Lipolysis FA esterification Triglycerides Glycerol-3P Glucose, amino acids, lactate, pyruvate FA Adipocyte

20. If the rate of lipolysis is more excessive than the rate of reestirification, FFAs accumulate and diffuse into the plasma, where they bind to serum albumin and are transported to tissue for oxidation Metabolism of adipose tissue FA Glycerol Lipolysis FA esterification FA Glycerol Triglycerides Glycerol-3P Glucose, amino acids, lactate, pyruvate FA Adipocyte Blood Tissues Albumin

21. This occurs in condition where the need for energy is increased as in 1. Starvation 2. Diabetes mellitus 3. During growth 4. Low carbohydrate diet 5. Certain infectious disease as tuberculosis Causes of excessive lipolysis

22. Lipolysis is carried out by a number of lipase enzymes which are present in adipose tissue 1. Hormone Sensitive triacyglycerol Lipase (HSL) 2. Diacylglycerol lipase 3. Monoacylglycerol lipase Mechanism of lipolysis TG DAG + FFA HSL DAG MAG + FFA DAG lipase MAG glycerol + FFA MAG lipase

23. FA Glycerol Lipolysis FA esterification FA Glycerol Triglycerides Glycerol-3P Glucose, amino acids, lactate, pyruvate FA Tissues Albumin Glycerol-3P Glycerokinase Glyconeogenesis Glycolysis Lipogenesis  oxidation FA ATP Blood Adipocyte

24. (fasting) (Stress) Insulin Hormonol regulation of HSL in adipose cells (In feeding) ++

25. Introduction Lipid breakdown is the process by which a molecule of fatty acid is degraded by the sequential removal of 2C units, producing acetyl CoA which can then be oxidized to CO2 and H2O by the TCA cycle. It occurs in many tissues, especially liver and muscle. Certain tissues such as brain, RBCs, and adrenal medulla are unable to oxidize fatty acids ( because they lack the necessary enzymes)

26. The Four Stages of Lipid Breakdown 1. Hydrolysis of TAG by Lipase (Lipolysis) 2. Activation of Fatty Acids 3. Transport into Mitochondria 4. β -Oxidation

27. Lipolysis It occurs in the cytosol of adipose cells. TAG is converted into glycerol and 3 fatty acids in 2 steps: 1. A hormone- sensitive lipase hydrolyses TAG at the C1 and C3 positions to form monoglycerol. 2. A monoglycerol specific lipase removes the remaining fatty acid.

28. Continue.. Glycerol produced cannot be metabolized by adipose tissue because it does not contain glycerol kinase. Glycerol is transported to the liver where it is phosphorylated, either to be used again to make TAG or to be converted to dihydroxyacetone phosphate (DHAP), a glycolytic intermediate. The free F.As produced are either re- esterified to TAG in the adipose tissue or travel in the blood to be taken up by the cells for oxidation. Glycerol produced cannot be metabolized by adipose tissue because it does not contain glycerol kinase. Glycerol is transported to the liver where it is phosphorylated, either to be used again to make TAG or to be converted to dihydroxyacetone phosphate (DHAP), a glycolytic intermediate. The free F.As produced are either re- esterified to TAG in the adipose tissue or travel in the blood to be taken up by the cells for oxidation.

29. Hormonal regulation of TAG degradation in the adipocyte.

30. Activation of Fatty Acids Fatty acids must be esterified to Coenzyme A before they can undergo oxidative degradation, be utilized for synthesis of complex lipids, or be attached to proteins as lipid anchors. Acyl-CoA Synthases (Thiokinases) of ER & outer mitochondrial membranes catalyze activation of long chain fatty acids, esterifying them to coenzyme A. This process is ATP-dependent. There are different Acyl-CoA Synthases for fatty acids of different chain lengths. PPi is cleaved by pyrophosphatase to 2 inorganic phosphate (2Pi)

31. Transport of Fatty Acyl CoA into Mitochondria Fatty acyl CoA is impermeable to inner mitochondrial membrane while enzymes for β -oxidation are present in the mitochondria Therefore after activation, the fatty acid (fatty acyl CoA) interacts with carnitine which helps in its translocation across the inner mitochondrial membrane. Transfer of the fatty acid moiety across the mitochondrial inner membrane involves carnitine. Carnitine Palmitoyl Transferases catalyzes transfer of a fatty acid between the thiol of Coenzyme A and the hydroxyl on carnitine

32. Carnitine-mediated transfer of the fatty acyl moiety into the mitochondrial matrix is a 3-step process: 1. Carnitine Palmitoyl Transferase I, an enzyme on the cytosolic surface of the outer mitochondrial membrane, transfers a fatty acid from CoA to the OH on carnitine. 2.Carnitine acylcarnitine translocase in the inner mitochondrial membrane mediates exchange of carnitine for acylcarnitine. 3.CarnitinePalmitoylTransferaseII,an enzyme within the matrix,transfers the fatty acid from carnitine to CoA. (Carnitine exits the matrix in step 2)  The fatty acid is now esterified to CoA in the matrix