Lipids Dr Sooad AlDaihan Biochemistry department Lipids Heterogeneous

Lipids Dr. Sooad Al-Daihan Biochemistry department

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

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

Functions ü 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 ü Storage form of energy-triglyceride ü Serve as structural components of cell membrane (PLs, glycolipids). ü Some are hormones e. g. steroid hormone (cortisol, aldosterone, sex hormones). ü 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

Digestion and Absorption of Lipids �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

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

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

Pancreatic lipase ü 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. ü converting TG to monoacylglycerol and free fatty acid. ü Triacylglycerol + 2 H 2 O 2 -monoacylglycerol + 2 fatty acid ü Unlike some pancreatic enzymes that are activated by proteolytic cleavage (e. g. trypsinogen), pancreatic lipase is secreted in its final form. ü However it only becomes efficient in the presence of colipase in the duodenum.

Phospholipid � 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 O O CH 2 – O – C - R 1 R 2 - C - O - CH O CH 2 – O – P – O - X Phospholipase A 2 O- ü 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.

Continue � 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 ü Phospholipase A 1 -cleaves the SN-1 acylchain. ü Phospholipase A 2 - 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 phosphatereleasing diacylglycerol containing head group. IV. Phospholipase D - cleaves after the phosphate.

Absorption of Lipids The end product of lipid digestion are: �MG �FA (short FA C 4 -C 10; long chain FA C 12 -C 18) �Glycerol �Lyso. PL �Cholesterol

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

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

�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)

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

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

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

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

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

Metabolism of adipose tissue 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 Glycerol Tissues Adipocyte FA Glycerol Albumin Lipolysis FA FA FA Triglycerides FA esterification Glycerol-3 P Blood Glucose, amino acids, lactate, pyruvate

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

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

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

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

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

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

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

Continue. . ü Glycerol produced cannot be metabolized by adipose tissue because it does not contain glycerol kinase. ü 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. ü 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.

Hormonal regulation of TAG degradation in the adipocyte.

Activation of Fatty Acids ü 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. ü Acyl-Co. A Synthases (Thiokinases) of ER & outer mitochondrial membranes catalyze activation of long chain fatty acids, esterifying them to coenzyme A. ü This process is ATP-dependent. ü There are different Acyl-Co. A Synthases for fatty acids of different chain lengths. ü PPi is cleaved by pyrophosphatase to 2 inorganic phosphate (2 Pi)

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

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 Co. A to the OH on carnitine. 2. Carnitine acylcarnitine translocase in the inner mitochondrial membrane mediates exchange of carnitine for acylcarnitine. 3. Carnitine. Palmitoyl. Transferase. II, an enzyme within the matrix, transfers the fatty acid from carnitine to Co. A. (Carnitine exits the matrix in step 2) The fatty acid is now esterified to Co. A in the matrix