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BIOCHEMISTRY SFA 2073 Lipid Metabolism

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    2. Digestion & Absorption • Lipids that gets into the digestive system are dietary lipids, normally free fatty acids, cholesterols and triglycerides (TAG) and many minor components. • Digestion starts in the duodenum portion of small intestine: - is mix with bile that contains HCO3ˉ ions and bile salts to solubilize fat. This process is called emulsification. The big lipids droplets are broken down into smaller droplets. (bile is made in liver and stored in gall bladder between meals. When there is food, bile is delivered to the intestine from gall bladder via bile duct)

    3. - TAG is acted by lipase secreted by pancreas liberating monoglyceride and two fatty acids. Monoglyceride, cholesterol and f.fasand bile salts form amphipathic micelles. These micelles keep the insoluble lipid components in soluble aggregates from which small amounts are released and absorbed by epithelial cells via diffusion. - Free fatty acids and monoglycerides then recombine into triacylglycerols at the smooth ER and together with cholesterols moves on to Golgi to be converted to chylymicrons. It enters interstitial fluid, then taken up by the lacteals in the intestinal wall and delivered to liver via hepatic portal vein for processing.

    4. exposure to a large aggregate of triglyceride, the hydrophobic portions of bile acids intercalate into the lipid, with the hydrophilic domains remaining at the surface. Such coating with bile acids aids in breakdown of large aggregates or droplets into smaller and smaller droplets.

    5. Pancreatic lipases hydrolyse triglyceride into monoglyceride and free fatty acids. The activity of this enzyme is clipping the fatty acids at positions 1 and 3 of the triglyceride, leaving two free fatty acids and a 2-monoglyceride. **Lipase is a water-soluble enzyme

    6. Lipids, and products of their digestion are transported through aqueous compartments within the cell as well as in the blood and tissue spaces in the forms LIPOPROTEINS Why in the form of LIPOPROTEINS? • Large portion of the lipids’ structures comprise of C-C &C-H rendering lipids hydrophobic in nature i.e lipids are insoluble in aqueous environmentthuscreates problem to its transport within body-medium which is aqueous in nature. Dietary triacylglycerols (Tag) & cholesterol and in-vivo Tag and cholesterol (synthesized in liver), must be converted to the soluble form to overcome the problem. This is achieved by forming LIPOPROTEINS

    7. Lipolysis • Is the breakdown of fat (Tag) stored in fat cells into free fatty acids + glycerol + mono & diglycerides which is catalysed by enzyme lipase • Induced by hormone epinephrine , norepinephrine, glucagon and adreno corticotropic hormone • the lipolytic products are then released into the blood • The free fatty acids bind to serum albumin and transport to tissues that require energy. The energy is generated by catabolic β-oxidation pathway (a 4 steps pathway/cycle)

    8. How the hormones induce lipolysis ? The hormones trigger 7TM receptors, which activate adenylate cyclase. This results in increased production of cAMP, which activates protein kinase A, which subsequently activate lipases found in adipose tissue. • β–oxidation of free fatty acid Fatty acid degradation and synthesis are relatively simple processes and essentially the reverse of each other.

    9. f.f.a first are activated to acyl-CoAcatalyse by Acyl-CoA synthase (ACosyn)prior to transport into mitochondria.

    10. acylCoA not permeable to inner mitochondria membrane, hence carried across bycarnitine carrier systeminto mitochondrion matrix. It is by conjugation to carnitine. • carnitine carrier system consisted of 2 enzyme-units CAT I & CAT II AcylCoA + Carnitine → Acyl-carnitine + Co-ASH Carnitine Acyl Transferase

    11. Carnitine (a quaternary ammonium compound)is hydrophilic amino acid derivative, produced endogenously in the kidneys and liver from lysine and methionine of diet’s meat and dairy products. Carnitine binds acyl residues conjugated with coenzyme A.

    12. Carnitine + Acyl-CoA Inner membrane + CoASH matrix CAT II Acyl-carnitine Acyl-CoA Intermembrane space ACosyn CAT I cytosol + CoASH Fatty acid Outer membrane CAT: carnitine Acyl transferase ACosyn: acyl-CoA synthetase Simplified mitochondrial layout

    13. Followed by (4 steps ) • - oxidation by FAD • - hydration • - oxidation by NAD+ • - thiolysis • The cycle then repeats on the larger fragment while acetyl-CoA fragment channeled to Krebs Cycle

    14. oxidation by FAD/Acyl-CoA DH : The activated fatty acid is oxidized to introduce a double bond. Step 1

    15. Hydration/Enoyl-CoA Hydratase: to introduce an oxygen via formation of alcohol Step 2

    16. oxidation by NAD+/Hydroxy-CoA- DH: the alcohol is oxidized to a ketone. Step 3

    17. Thiolysis- Thiolase/CoA-SH : cleaving of the acylCoA into two fragments, acetyl CoA and an acylCoA of fatty acid chain two carbons shorter. Step 4

    18. Steps: 1 and 2 3 and 4

    19. β-oxidation of unsaturated fatty acids poses a problem. Unsaturated f.a are the cis type. This prevents the formation of the required bond orientation, trans-δ2 bond, in the enoyl intermediate. These situations are handled by an additional of two enzymes.

    20. Anabolism Of Fatty Acidin Human • Process occurs in cytoplasm of liver (major) and adipose tissue cells. • Fatty acids are formed by the following 3 rxn-stages: i- acetyl-CoA Carboxylase rxn ii- fatty acid synthase rxn iii- desaturase rxn • This process is the de novo synthesis of F.A • The initiator substrate acetyl-CoA is the product of β-oxidation catabolic pathway

    21. Cytoplasm Mitochondria Acetyl CoA Acetyl CoA synthesis citrate β-oxidation citrate Fatty Acid oxaloacetate Fatty Acid ATP-citrate lyase NADH oxaloacetate Citrate synthase NADH malate NAD+ malate Malate DH NADP+ NAD+ Malic enzyme NADP+ pyruvate NADPH NADPH pyruvate transporter Malate-oxaloacetate shuttle: Transfer OF Acetyl CoA from Mitochondria to cytoplasm

    22. Oxidation Fatty Acid & Cholesterol Steroid hormones Ketone bodies Glucose Pyruvate Fatty Acids Ketogenic Amino Acids ACETYL-CoA SOURCES AND UTILIZATION OF ACETYL-CoA

    23. Acetyl-CoA Carboxylase rxn • Initiator to fatty acid synthesis is acetyl-CoA • Acetyl-CoA carboxylase catalyses carboxylation of acetyl-CoA to malonyl-CoA via 2-steps reaction. • The enzyme is biotin bound. In mammals acetyl-CoA carboxylase is a large enzyme controlled by conversion inactive ══> active (inactive: protomers (4 subunits; one biotin); active: 1 unit) conversion promoted by citrate, but inhibited by fatty acyl CoA.Also by hormonal controlled: in liver by glucagon – PO4rylation to inactive form; in adipose tissue by adrenalin (epinephrin)– PO4rylation to inactive form Additional note • Acetyl-CoA originated from pyruvate in mitochondria and transported to cytosol as citrate by condensing with oxaloacetate • In cytosol citrate is broken down to yield acetyl-CoA and oxaloacetate by ATP-citrate lyase. • Acetyl-CoA undergoes carboxylation by Acetyl-CoA carboxylase to malonyl-CoA

    24. Figure at right is expansion of reaction in figure on left

    25. reaction at site 2

    26. ATP-dependent carboxylation of the biotin, carried out at one active site (1) • transfer of the carboxyl group to acetyl-CoA at a second active site (2). • Reaction is spontaneous, HCO3- + ATP + acetyl-CoA → ADP + Pi + malonyl-CoA

    27. Fatty acid synthase rxn • The reaction is a multi-steps . • The enzyme(in mammal) is a very large polypeptide of many domains that includes an acyl carrier protein domain. • Has a number of prosthetic grps. • Individual domain catalyses a single step . • the precursor of fatty acid synthesis is malonyl-CoA • the initial action is binding of acetyl-CoA (2C) and malonyl-CoA (3C) to specific domain of FAS leading to formation of acyl-ACP intermediates -5C (steps 1&2)

    28. Followed by formation of β-ketoacyl-ACP (4C) with evolution of CO2 (step 3)

    29. β-ketoacyl is reduced to an alcohol, by electron transfer from NADPH (step 4). • Dehydration yields a trans double bond (step 5). • Reduction at the double bond by NADPH yields a saturated Acyl-ACP chain- 4C (step 6). This is 1 cycle.

    30. Acyl-ACP and malonyl ACP then repeat step 3 and reaction proceeds to step 7.

    31. Acyl chain lengthens by 2C / cycle. • Elongation process stops when acyl 16C is formed. Hydrolysis of the ester bond takes place with liberation of palmitate.

    32. FAS **The active enzyme is a dimer of identical subunits. All of the reactions of fatty acid synthesis are carried out by the multiple enzymatic activities of fatty acid synthaseFAS

    33. REGULATION of f.f a synthesis • The major site of fatty acid synthesisregulation is atreaction catalysed by acetyl-CoA carboxylase (ACC). ACC requires a biotin co-factor

    34. Activity of ACC is associated with conformational change of the enzyme, and conc. of citrate and palmitoyl-CoA. When [citrate] is high, monomeric form associates to the multimeric form. Active conformation is the multimeric form. When [palmitoyl] is high, multimeric form dissociates into monomeric,it becomes inactive. citrate (multimeric)n + Pi n monomeric –PO4 active inactive palmitoyl

    35. Catabolism Of Triglycerides (TG) • Initial rxn is in small intestine where TG is mixed with bile salt. • Bile salt are steroids with detergent properties. 2 most abundant componants are cholate and deoxycholate, and they are normally conjugated with either glycine or taurine

    36. Taurocholic acid. In mammal it exists as Na+ salt. In medical use, it is administered as cholagogue and choleretic. Glycocholic acid (Cholic acid+ glycin). It occurs as a sodium salt in the bile of mammals

    37. Starts by break-up of the glyceride (TG) into fatty acids and monoacylglycerol by pancreatic lipases. This step takes place because TG cannot be transported across the plasma membrane of the intestinal wall cells (enterocytes) due to its size.

    38. The 2 products are transported into the cell. Once in the cell, recombination occurs and triacylglyerols TG1 are reformed. • TG1 is combined with dietary cholesterol, newly synthesized phospholipids and protein into compound chylomicrons (a large, low-density lipoproteins).

    39. Lipoprotein lipase (synthesize by a number of sources) acts on TG1 portion in the chylomicron liberating F.F.A and glycerol. F.F.A is metabolised by either: - converted to new TG - catabolic pathway(β-oxidation) - used in membrane synthesis

    40. The glycerol is transported to and absorbed by the liver or kidney where it is converted to glycerol-3-phosphate by the enzyme glycerol kinase,GK. Glycerol 3-phosphate (especially from hepatic) converted into dihydroxyacetonephosphate (DHAP) then glyceraldehyde-3-phosephate(G3P) to join glycolysis and gluconeogenesis pathway.

    41. IN INTESTINE TG1 in chylomicron Lipoprotein lipase F.F.A Glycerol Glycerol kinase TG Glycerol-3-PO4 Catabolism β-oxidation Membrane synthesis TG phospholipids Glucose

    42. Anabolism Of Triglyceride • Precursor is L-glycero-3-phosphate • Proceed by condensation with acyl-CoA to form lysophospha- tidic acid (l.p.a), catalyse by enzyme E1 Glycerol PEP L-glycerol-3-PO4 2 1 *1 is glycerol-3-PO4 DH ; 2 is glycerol kinase *E1 isglycerol-3-PO4 acyltranferase

    43. Further reactions on l.p.a till formation of TG

    44. Cholesterols

    45. CHOLESTEROL • Is a soft, fat-like, waxy substance found in the bloodstream and membrane of cells (especially of the liver, spinal cord), and myelin sheaths and some hormones. • require by cells as a precursor to bile acids. • it is transported in the circulatory system within lipoproteins.

    46. The most abundant of the steroids **Steroids are complex derivatives of triterpenes They are characterized by a carbon skeleton consisting of four fused rings. 

    47. normal adult utilized ~1 gram of cholesterol daily. Approximately 70% of the amount produces by the liver. The other 30% comes from dietary intake • Cholesterol is the precursor for all steroids. It is a common component of animal cell membranes and functions to help stabilize the membrane. Thus it is a crucial molecule *high levels of it in the blood may contribute to atherosclerosis.