Metabolism of dietary lipids .  -Oxidation of fatty acids. Ketone bodies.

1. Lipid Metabolism • Metabolism of dietary lipids. • -Oxidation of fatty acids. • Ketone bodies. • Biosynthesis of fatty acids. • Biosynthesis of triacylglycerols. • Biosynthesis of cholesterol, steroids. • Plasma lipoproteins.

2. Biochemistry of Lipids • Classification. • 1- Storage lipids. • 2- Structural lipids in membranes. • 3- Lipids as signals, cofactors and pigments. • Storage lipids • Fatty acids are hydrocarbon derivatives. • - C4 to C36. • - Saturation. • - Nomenclature. • - Physical properties. • Triacylglycerols. • - Simple vs. complex triglycerides. • - Function: provide stored energy and insulation. • Waxes. • - Functions: serve as energy stores and water repellents.

3. Structural lipids in membranes • Types of membrane lipids: • 1- Glycerophospholipids: • - Phosphatidic acid. • 2- Sphingolipids: • - Sphingosine. • - Biological recognition. • - Degradation. • 3- Sterols: • - Steroid nucleus. • - Functions. • Lipids as signals, cofactors and pigments • Phosphatidylinositols act as intracellular signals. • Eicosanoids carry messages to nearby cells. • - Prostaglandins. • - Thromboxanes. • - Leukotrienes.

4. Triacylglycerols • Steroid hormones carry messages between tissues. • Vitamins A and D are hormone precursors. • Vitamins E and K are oxidation-reduction cofactors.

5. Lipid Classes

6. Glycerophospholipids “Phospholipids”

7. SphingoLipids

8. Metabolism of dietary lipids and -oxidation of fatty acids • Advantages of using fats as storage form of energy • The carbon atoms are more reduced than those of sugars  oxidation of fats yields more energy. • They are hydrophobic, unhydrated, no extra weight of hydration. • They don’t increase osmolarity inside cells because they are not soluble. • Digestion, mobilization and transport of fats • cells can obtain fatty acid fuels from three sources: • 1- fats consumed in the diet (60-150 gm/day , TG 90% , cholesterol) • 2- fats stored in cells as lipid droplets (adipocytes) • 3- fats synthesized in one organ to be exported to another. (excess CHO is converted to fats in the liver to be exported to other cells)

9. dietary fats are absorbed in the small intestine • dietary lipids are not digested to any extent in the mouth or stomach in adults. • The rate of action of acid-stable lipase is very slow in adults, because it is active only at neutral pH. • In infants this enzyme may have a role. • In the duodenum : emulsification of the dietary lipids occurs. • Lipids are insoluble  hydrolysis occurs only at the interfacesemulsification increase surface area of lipid droplets . • - this occurs by: • 1- bile salts act as detergents. • bile salt = bile acid (steroid nucleus) + glycin or taurine. • 2- mechanical mixing due to peristalsis  Forming of micelles

10. Hydrolysis of Choesteryl ester Cholesteryl esterase

11. Hydrolysis of Triglycerides * Colipase enzyme secreted by the pancreas to anchor and stabilize the lipase at the lipid- aqueous interface.

12. Hydrolysis of Phospholipids (Lysolecithin) Phospholipase A2 : secreted from pancreas, removes the F.A from C2

13. hydrophilic Hydro-phobic core Brush membrane * Absorption of lipids by intestinal mucosal cells The primary products of dietary lipid degradation with the bile salts from mixed micelles. Short and medium chain length F.A don’t need micelles formation to be absorbed (pass directly)

14. Resynthesis of triacylglycerol and cholesteryl esters by the intestinal mucosal cell

15. Resynthesis of triacylglycerol and cholesteryl esters by the intestinal mucosal cell • long fatty acid fatty acyl synthetase (thiokinase) fatty acyl CoA • short and medium F.A are released into the portal circulation where they are carried by serum albumin to the liver. • - 2-monoacylglycerol + 2 fatty acyl CoA acyltransferase triacylglycerol • - also phospholipids, cholesterol esters are resynthesized by a family of acyl transferases. • Secretion of lipids from intestinal mucosal cells • newly synthesized triacylglycerol and cholesterol esters are packed as oily droplets surrounded by protein and phospholipid and unesterified cholesterol  increase solubility called (chylomicrons) . • *lipoproteins : lipid-binding proteins found in the blood. Responsible for transporting of cholesterol, cholesterol esters, phospholipid and triacylglycerols between organs. • * Apolipoprotein (free form without lipid) + lipids = lipoproteins • spherical structure with hydrophobic core and hydrophilic surface. These aggregates have various densities (chylomicrons, very low density lipoprotein VLDL, LDL, HDL, VHDL

16. Chylomicrons

17. chylomicrons move from intestinal mucosa into the lymphatic system then enter the blood then carried to muscle and adipose tissue mainly. And also to other tissues (heart, lung and kidney) where the chylomicrons are degraded. • *The protein moieties of apoproteins are recognized by receptors on cell surfaces. • * Degradation of chylomicrons • Triglycerides of chylomicrons are degraded to free fatty acid and glycerol by lipoprotein lipase that is activated by (apo C-).. • free fatty acids are oxidized for fuel or resynthesized for storage. • * glycerol is converted to glycerol 3-phosphate in the liver • * remaining of chylomicrons are taken by the liver (that contains cholesterol, cholesterol esters, phospholipids, proteins and some T.G) Chylomicrons

18. Bile salts are synthesized from cholesterol in the liver and stored in the bilary gland and act as detergent (amphipathic) Formation of micelles increase the surface of lipids exposed to the enzymes which is water soluble. T.G lipase 2-monogycerol + 2 F.A Cholesterol ester cholesterol

19. * Use of dietary lipids by the tissues • T.G in chylomicrons are broken down mainly by skeletal muscles and adipose tissue. other organ can utilize T.G like heart, kidney, liver and lung. • T.G in chylomicrons are degraded into free F.A and glycerol by lipoprotein lipase. This enzyme is synthesized mainly by skeletal muscle and adipose tissue. • T.G free F.A + glycerol • * Fate of fatty acids • -free fatty acid may directly enter the adipocyte or myocyte to be utilized or can be transported with the blood to other cells to be utilized there. F.As are associated with serum albumin until they are taken by other cells. • -F.As in skeletal muscles are oxidized to produce energy by -oxidastion. • F.As in adipocyte are reesterified to produce T.G to be stored. • * Fate of glycerol • glycerol that is released from T.G hydrolysis is taken by the liver to produce glycerol 3-phosphate and enter glycolysis or gluconeogenesis. • * Fate of chylomicron remnants • - it contains cholesterol, cholesterol esters, phospholipids, proteins and little T.G. • - chylomicrons remnants are taken up by the liver where they are hydrolyzed to their components and can be recycled.

20. Oxidation Metabolism of glycerol T.G lipase fatty acids + glycerol Glycerol kinase In liver Glycerol 3-phosphate dehydrogenase Triose phosphate isomerase

21. Hormones trigger mobilization of stored TG. That stored in adipocyte Low level of glucose trigger the mobilization of triacylglycerols

22. Decrease blood glucose increase epinephrine and increase Glucagon activation of lipase increase hydrolysis of TG from adipocytes Can’t be metabolized by adipocytes Epinephrine Glucagon

23. * Metabolism of dietary lipids • A) Limited processing of lipids in mouth and stomach. • B) Emulsification of dietary lipids in small intestine. • - bile salts • - mechanical mixing due to peristalsis • C) Enzymatic degradation of dietary lipids by pancreatic enzymes in the small intestine. • - T.G degradation (pancreatic lipase) • - P.L degradation (phospholipase A2, lysophospholipase) • - cholesterol ester degradation (cholesterol esterase) • D) Absorption of lipids by intestinal mucosal cells. • - formation of mixed micelles, F.A + 2-monoacylglycerol + cholesterol + bile salts • E) Resynthesis of T.G and cholesterol esters by intestinal cells • - F.A thiokinase fattyacyl CoA • - 2-monoacylglycerol + 2 fatty acyl acyl transferase T.G • - cholesterol + fattyacyl CoA acyl transferase cholesterol ester • F) Secretion of lipids from intestinal mucosal cell • chylomicrons transferred by exocytosis from intestinal cells into lymphatic system.

24. * Metabolism of T.G stored in adipocytes and -oxidation • Mobilization of F.A from stored T.G in adipose tissue. • T.G lipase 2-monoacylglycerol glycerol + 3 F.A • * Fate of glycerol • - glycerol can’t be metabolized by adipocytes because of the lack of glycerol kinase. • So it released and transported to liver to be metabolized. • * Fate of free fatty acid • - free fatty acid from adipocytes transferred by blood bounded to albumin to other organs to be used as fuels. • - brain, nervous tissues, erythrocytes and adrenal medulla cannot use plasma free fatty acid as fuel, regardless of blood level of F.A. • * Different fates of T.G in liver and adipose tissue • - in adipose tissue : T.G is stored in the cytosol of the cell and it is ready for mobilization when the body requires it. • - in liver : little T.G is stored, but most is exported and packaged with cholesterol and cholesterol esters phospholipid lipoproteins. Then secreted into the blood.

25. The End

26. * Hormonal control of lipid digestion * the hydrolytic enzymes that degrade lipids are secreted from pancreas and this is controlled by hormones. Cells from lower duodenum and jejunum produce Cholecystokinin Cause the gall bladder to contract and to release its bile salts also it decrease stomach contraction (gastric motility) Increase release of bicarbonate solution to increase pH to give appropriate pH for enzymatic digestion activity. PANCREAS GALL BLADDER

27. * Disorders of dietary lipid metabolism • 1- lipid malabsorption • Inability of body to absorb the lipids and resulted in loss of lipids including fat soluble vitamins A,D,E,K • and occurred at different conditions : • 1- loss of bile salts. • 2- loss of pancreatic enzymes. • 3- deficiency of some hormones. • 2- Congenital abeta lipoproteinemia • Deficiency of apo B-48 from intestinal cells decrease in synthesis of chylomicrons accumulation of T.G in intestinal mucosal cells. • 3- Familial Lipoprotein Lipase deficiency (Type I hyperlipoproteinemia) • Resulted from deficiency of lipoprotein lipase and resulted in massive chylomicronemia • inability to use T.G from chylomicrons • 4- Familial Type III hyperlipoproteinemia (familial dysbeta lipoproteimemia) • Defective in taking up the chylomicron remnants from plasma by the liver accumulation of chylomicron remnants (cholesterol, cholesterol esters, … ) • This due to deficiency of apolipoprotein E