Lipids PDF

All diagrams and pictures used in this power point are only for teaching purpose 1 LIPID METABOLISM 1 2  Lecture Learning Outcome/Outline Students should be able to identify/describe: Structure and R...

All diagrams and pictures used in this power point are only for teaching purpose 1 LIPID METABOLISM 1 2  Lecture Learning Outcome/Outline Students should be able to identify/describe: Structure and Role of Lipids Main classes of lipid, Fatty acids: nomenclature and structure (revision) Fatty Acid Biosynthesis Biosynthesis of saturated fatty acids Elongation of fatty acids, Unsaturation of fatty acids & Essential fatty acids Regulation of fatty acid synthesis Acylglycerol Metabolism and Mobilisation of Lipids Biosynthesis and hydrolysis of triacylglycerol Glycerophospholipids: biosynthesis and hydrolysis Acylglycerols as energy source for the body Mobilisation of adipose tissue lipids Fatty Acid Oxidation and Ketone Bodies Outline of fatty acid oxidation (β oxidation) including stoichiometry & regulation Odd carbon fatty acid and unsaturated fatty acid oxidation Regulation of beta oxidation Ketone bodies: synthesis and ultilisation Overview of Cholesterol biosynthesis- bile and steroid synthesis 3 LIPIDS Generally all lipids are associated ‘either’ or ‘actually’ to the fatty acids. Soluble in non-polar solvents and insoluble in polar solvents. Lipids are not polymers http://dientutieudung.vn/ra-pho/i6313-anh-macro-lung-linh-hat-suong-mai/ 2 4  (II) Compound Lipids Phospholipids Glycolipids Sulpholipids Aminolipids (Proteolipids) (III) Derived Lipids Lipoproteins Fatty acids (I) Simple Lipids Monoacylglycerol 1.Neutral fats Classification Diaclglycerol (triacylglycerol) 2. Waxes of Lipids Glycerol 3. Cholestrol esters Cholesterol (IV) Miscellaneous Steroids 1. Aliphatic Hydrocarbons Vitamins A,D, 2. Carotenoids 3. Squalene 4. Vitamins E and K 5 Fatty Acids O R C OH #1 Carbon Acid Group O R C OH Polar End - Hydrophilic End Non-polar End - Hydrophobic End (Fat-soluble tail) 3 6  Saturated Fatty Acids O 8 7 6 5 4 3 2 1 CH3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 C OH Octanoic Acid 7 Unsaturated Fatty Acids O 8 7 6 5 4 3 2 1 CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 C OH 3 - Octenoic Acid O 8 7 6 5 4 3 2 1 CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 C OH 3, 6 - Octadienoic Acid Short hand: 8:1 (Δ3) 8:2 (Δ 3,6) 4 8  Cis and Trans Fatty Acids H H O CH3 (CH2 )7 C C (CH 2 )7 C OH 10 9 Cis 9 - Octadecenoic Acid (oleic) H O CH3 (CH 2 )7 C C (CH2 )7 C OH H Trans 9 - Octadecenoic Acid (elaidic acid) 9 TYPES OF FATTY ACIDS (according to the number of double bonds) Saturated (No double bond) Monounsaturated (1 double bond) Polyunsaturated (>1 double bond) 5 10  Naturally-occurring fatty acids O R CH 2 CH CH CH 2 CH CH CH 2 C OH 7 6 5 4 3 1. Cis form 2. Not conjugated --- isolated double bond. 3. Even numbered fatty acids. 11 O 6 1 2 3 4 5 OH Linoleic Acid 18:2 Δ9, Δ 12 ω 6 unsaturated fatty acid O 1 3 2 OH Linolenic Acid 18:3 Δ 9, Δ 12, Δ 15 ω 3 unsaturated fatty acid Obtained from Plant oils, Fish oils. 6 12  CLASSIFICATION OF FATTY ACIDS PRESENT AS GLYCERIDES IN FOOD FATS (I. Saturated Fatty Acids) Common Name Systematic Name Formula Butyric Butanoic CH3(CH2)2COOH Caproic Hexanoic CH3(CH2)4COOH Caprylic Octanoic CH3(CH2)6COOH Capric Decanoic CH3(CH2)8COOH Lauric Dodecanoic CH3(CH2)10COOH Myristic Tetradecanoic CH3(CH2)12COOH Palmitic Hexadecanoic CH3(CH2)14COOH Stearic Octadecanoic CH3(CH2)16COOH Arachidic Eicosanoic CH3(CH2)18COOH 13 Common and Systematic Names of Fatty Acids (II Unsaturated Fatty Acids) Common Name Systematic Name Formula A. Monoethenoic Acids Oleic Cis 9-octadecenoic C17H33COOH Elaidic Trans 9-Octadecenoic C17H33COOH B. Diethenoic Acids Linoleic 9,12-Octadecadienoic C17H31COOH C. Triethenoic Acids Linolenic 9,12,15-Octadecatrienoic C17H29COOH Eleostearic 9,11,13-Octadecatrienoic C17H29COOH D. Tetraethenoic Acids Moroctic 4,8,12,15-Octadecatetraenoic C17H27COOH Arachidonic 5,8,11,14-Eicosatetraenoic C19H31COOH 7 14 15 Fatty Acid Composition of Fats of Animal and Plant Origin 8 16  FATS http://www.eatright-livewell.com/blog 17 Melting Points and Solubility in Water of Fatty Acids Melting Point As the chain length increases, the solubility in water decreases and the melting point increases H2O Solubility in H O 2 Chain Length 9 18  Effects of Double Bonds on the Melting Points M.P. F. A. M. P. (°C) 16:0 60 16:1 1 18:0 63 18:1 16 18:2 -5 18:3 -11 20:0 75 # Double bonds 20:4 -50 The melting point decreases with increasing number of double bonds 19 FAT AND OILS 10 20  Assimilation of dietary fat (revision) Lingual lipase (mouth) Secreted by the dorsal surface of the tongue (Ebner’s gland) digests TGs with short fatty acids 8 7 1 6 2 5 3 4 21 Adipose Tissue Electron micrograph Oil Red O Stain Adipocyte has the capacity to expand to accommodate increasing amount of fat (TGs) that need to be stored. The size can vary: 20-200nm (diameter) 11 22  Fat from Diet & Adipose Cells Triacylglycerols Triglycerides are the major form of stored energy in the body. Insulin mediates/stimulates storage of fatty acids in the form of triglycerides. Hormones (glucagon, epinephrine, ACTH) trigger the release of fatty acids from adipose tissue 23 Why Fatty Acids? Two reasons: 1.The carbon in fatty acids (mostly CH2) is almost completely reduced (so its oxidation yields the most energy possible). 2. Fatty acids are not hydrated (as mono- and polysaccharides are), so they can pack more closely in storage tissues 12 24 URAK1 Fatty acid metabolism Acetyl CoA Lipogenesis Esterification Triacylglycerol Hydrolysis FATTY Triacylglycerol Fat (Diet) ACID Fat (stores) Lipolysis Beta-oxidation Cholesterol, Acetyl CoA Steroids Ketogenesis TCA/KREBS cycle Ketone bodies 25 Synthesis of Fatty Acids Happens in cytosol 13 26 Slide 25 URAK1 UMAH RANI A/P KUPPUSAMY, 20/11/2020  Source of Acetyl CoA for Fatty Acid Synthesis: Glucose pyruvate MITOCHONDRION CYTOSOL Tricarboxylate transport system ATP-citrate lyase Citrate synthase Malate dehydrogenase Pyruvate carboxylase Malic enzyme +CO2 27 Two important reactions : 1. Acetyl-CoA carboxylase 2. Fatty acid synthase 14 28  1. Acetyl CoA carboxylase Irreversible two-step reaction Animal cells - one multifunctional polypeptide i) Biotin carboxylase ii) Biotin carrier protein iii) Transcarboxylase Require a biotin prosthetic group 29 Acetyl CoA + ATP + HCO3- Malonyl CoA + ADP + Pi + H+ ATP Biotin carboxylase Biotin Biotin Biotin Biotin serves as a carrier carrier temproary carbonyl protein protein carrier Biotin Transcarboxylase Biotin carboxylase activates CO2 by attaching it to a nitrogen in biotin ring in an ATP-dependent Acetyl CoA reaction. Transcarboxylase transfers the activated CO2 from the biotin to acetyl- CoA to form malonyl- CoA. Malonyl CoA The committed step in fatty acid synthesis is the formation of malonyl-CoA 15 30  Fatty Acid Synthesis Requires NADPH 1 2 31 2. Fatty Acid Synthase Dimeric multienzyme complex – more stable Two fatty acids can be synthesised simultaneously Uses acetyl-CoA and NADPH (malonyl CoA ; donor of acetate in the elongating fatty acid chain) Produces palmitic acid (16:0) Enzyme component Function Acyl carrier protein (ACP) Carries acyl groups in thioester linkage Acetyl-CoA- ACP Transfers acyl group from HD transferase (AT) CoA to Cys residue of KS KS Malonyl-CoA-ACP Transfers Malonyl group transferase (MT) from CoA to ACP β-Ketoacyl-ACP synthase Condenses acyl and (KS) (condensing enzyme) malonyl groups Condensation β -Ketoacyl-ACP reductase Reduces β-keto group to (KR) β-hydroxy group Keto-reduction β -Hydroxyacyl-ACP Removes H2O from β - KS dehydratase (HD) hydroxyacyl-ACP, creating HD Condensation double bond Enoyl-ACP reductase (ER) Reduces Double bond, Enoyl reduction forming saturated acyl- ACP Thioesterase (TE) Liberates the palmitate 16 32  H H OH CH3 O HS (CH2)2 N C (CH2)2 N C C C CH2 O P O CH2 Ser Polipeptide - O O H CH3 O Phosphopentotheine group ACP H H OH CH3 O O HS (CH2)2 N C (CH2)2 N C C C CH2 O P O P O CH2 - - O O H CH3 O O O Adenine H H -2 H H O3PO OH CoA 33 Initiation: Part I Initiation: Part II KS ACP KS ACP ACP KS ACP KS ACP KS KS ACP ACP KS ACP KS Acetyl CoA is first added to ACP, then transferred Now Malonyl-CoA to β-Ketoacyl-ACP synthase Is added to ACP (KS). (similar manner as the growing fatty acid chain after completion of each cycle) 17 34  Elongation Cycle in Fatty Acid Biosynthesis Malonyl-ACP ACP S condensation β-reduction dehydration enoyl-reduction NADPH ACP NADPH C O ACP ACP ACP + + H S + H+ CH2 CO2 S + S H2O + S NADP C O NADP C O C O C O C O - H C O Ketoacyl CH2 Ketoacyl CH2 Dehydratase Enoyl CH2 + synthase reductase C H reductase C O H C OH CH2 ACP CH3 CH3 CH3 CH3 S Acetoacetyl-ACP D-3-OHacyl-ACP Enoyl-ACP Acyl-ACP C O (β-Hydroxyacyl-ACP) CH3 Acetyl-ACP 35 Lengthened fatty acid chain is then translocated to KS. Another malonyl group is added to the SH group of ACP. Malonyl CoA H KS KS ACP KS KS ACP KS ACP KS ACP 18 36  https://www.youtube.com/watch?v=Dc3_LLXsguw Palmitate release is catalysed by palmitate thioesterase 37 The Total Reaction First Round:4 carbons long (butyryl) Second Round: 6 carbons long Third Round: 8 carbons long Fourth Round: 10 carbons long Fifth Round: 12 carbons long Sixth Round: 14 carbons long Seventh Round: 16 carbons long (palmityl) Total of seven rounds to make the product, which is recognized and released by palmitate thioesterase. 8 Acetyl CoA + 7ATP + 14 NADPH + 14H+ --> palmitate + 8 CoA + 6H2O + 7 ADP + 7Pi + 14 NADP+ 19 38  Elongation and Desaturation (ER of animals and plants) Fatty acids are elongated by other systems after palmitate (16C). Elongation is Mammals lack the catalyzed by enzyme required to enzyme systems in desaturate past Δ9. ER, similar to that of fatty acid synthase. Uses molecular Oxygen Steps similar to FA synthase (O2) as the electron EXCEPT that acceptor and leads to 1. Fatty Acyl-CoA (not ACP) the oxidation of both the is the substrate Fatty Acid (introduction for condensation with of the double bond) and malonyl-CoA NADH 2. Catalyzed by individual ER localized enzymes, not a single multiprotein complex 39 Regulation of Fatty Acid Synthesis: 1) Allosteric: Citrate Long chain FAs + Acetyl CoA Carboxylase - Acetyl CoA Malonyl CoA CO2, Biotin, ATP ( Malonyl CoA inhibits Carnitine Acyl Transferase I) 2) Hormonal regulation of Acetyl CoA Carboxylase Glucagon polymer protomer Insulin 20 40  Biosynthesis of TAGs and phospholipids 41 Biosynthesis of TAGs and Biosynthesis of TAGs (Part 1) (Part 2) Two pathways to glycerol-3-phosphate L-Glycerol 3-phosphate Acyl Acyl-CoA synthetase transferase 1 1-Acylglycerol-3-phosphate Acyl Acyl-CoA Glycerol 3-phosphate Glycerol transferase synthetase dehydrogenase kinase kinase 2 1 2 L-Glycerol 3-phosphate 1,2-Diacylglycerol phosphate (phosphatidic acid) 21 42  Biosynthesis of TAGs (Part 3) Phosphatidate Phosphatidic acid phosphatase Here the pathways branch to Acyl TAG or transferase Glycerophospholipid phospholipid. Triacylglycerol 43 Regulation of TAG Biosynthesis Insulin and glucagon are key regulators. insulin glucagon 22 44  Biosynthesis of Glycerophospholipid Choline Choline ATP Phosphatidate kinase Phosphatidate H2O Cardiolipin ADP phosphatase CDP-DG Pi synthase Phosphocholine CTP Pi CTP Phosphocholine CTP cytidyltransferase CDP- 1,2-Diacylglycerol diacylglycerol Pi Phosphatidyl inositol Diacylglycerol AcylCoA inositol Acyltransferase synthase CDP-choline CMP CDP-choline CoA diacylglycerol Phosphatidyl phosphocholine inositol transferase CMP Triacylglycerol ATP kinase Phosphatidylcholine ADP (-CH3)3 Phosphatidylethanolamine N- Phosphatidyl inositol methyltransferase 4-phosphate ATP Serine Phosphatidylethanolamine kinase ADP CO2 Ethanolamine Phosphatidyl inositol4,5 Phosphatidylserine bisphosphate 45 Glycerophospholipid Membrane component. O Bile component (PC). O CH2 O C R1 Precursor of second messenger. R2 C O C H O CH2 O P O X Precursor of prostaglandin and - O compounds of similar function. Lung surfactant X H -H; phosphatidic acid HO H HO OH -CH2CH2NH3+; phosphatidylethanolamine OH H ; phosphatidylinositol H H -CH2CH2N(CH3)3+; phosphatidylcholine H OH -CH2CH(NH3+)COO-; phosphatidylserine- CH2CH(OH)CH2OH; phosphatidylglycerol 23 46  Phospholipid Hydrolysis Phospholipase A1 O O CH2 O C R1 R2 C O CH O CH2 O P O X Phospholipase A2 - O Phospholipase C Phospholipase D 47 Lipid-based Hormone Biosynthesis Prostaglandins play a key role in inflammation at the site of damage/injury https://www.cvphysiology.com/Blood%20Flow/BF013 24 48  Pancreatic lipase Intestine Hepatic Lipase Liver Triacylglycerol Hydrolysis Lipoprotein Lipase Capillaries/ chylomicrons Hormone Sensitive Lipase Adipocytes TG + 3H2O Lipase Glycerol + 3 Fatty Acid + 3H+ Glycerol 3- Fatty acid Used in Dihydroxyacetone Phosphate oxidation other phosphate processes Acetyl CoA Glycolysis Gluconeogenesis Cholesterol Ketone Bodies TCA cycle 49 Adipose Tissue Fat Mobilisation PLASMA ADOPOSE Insulin ( –) TISSUE Epinephrine ( +) Insulin TG (+) TG Insulin ( +) Hormone sensitive lipase Epinephrine (-) LIPOLYSIS Lipoprotein LIPOGENESIS lipase Glycerol Glycerol Fatty Glycerol-3-P Fatty Acyl Acid Acid CoA Insulin ( +) Epinephrine (-) DHAP Glucose Glut-4 Glucose Glut-4 25 50  The utilization of fatty acids as fuel require 3 stages of processing 1. The lipids must be mobilized from the fat depots (adipose); Triglycerides are degraded to fatty acids and glycerols, then transported to energy requiring tissues. 2. At these tissues, fatty acids must be activated and transported into the mitochondria 3. The fatty acids are broken down in a step by step fashion into Acetyl CoA http://www.cell.com/cell-metabolism/abstract/S1550-4131(13)00058-2 51 Mobilization of Fat Epinephrine/glucagon Adipocyte 1 2 3 4 5 6 Blood stream Myocyte (Muscle) 26 52  Oxidation of Fatty acid 53 Fatty Acid w b a Oxidation 3 2 1 α–oxidation - Oxidation of branched fatty acids. Eg. Phytanic acid. Phytanic acid is a significant constituent of milk lipids and animal fats - The C a is hydroxylated and then oxidatively decarboxylated (release of CO2). Then normal beta oxidation - Occurs in brain tissues and liver (in peroxisome, than in mitochondria) ω-oxidation (Happens in some species of animals. Alternative pathway to β – oxidation. Occurs in ER. β - oxidation Most common. Occurs in mitochondria 27 54  Refsum’s disease Neurocutaneous syndrome characterized by accumulation of phytanic acid in plasma and tissues. Patients are unable to degrade phytanic acid due to deficiency of phytanic acid oxidase (first step in phytanic acid α oxidation retinitis pigmentosa Symptoms: Peripheral polyneuropathy, cerebellar ataxia, retinitis pigmentosa, ichthyosis (rough, dry scaly skin) http://www.keywordsking.com/cmVmc3VtICBkaXNlYXNl/ http://skinawareness.org/tag/ichthyosis/ ichthyosis 55 Beta Oxidation is the main catabolic pathway for fatty acids ω This bond is cleaved 28 56  CoA activates Fatty Acids for oxidation Acyl-CoA synthetase condenses fatty acids with CoA, with simultaneous hydrolysis of ATP to AMP and PPi Formation of a CoA ester is expensive energetically Reaction just barely breaks even with ATP hydrolysis But subsequent hydrolysis of PPi drives the reaction strongly forward Acyl-CoA synthetase O Acyl-CoA synthetase O R C O- + ATP + CoA SH R C S CoA + AMP + PPi O H2O O - + R C O + ATP + CoA SH + H2O R C S CoA + AMP + 2 Pi + H 57 The activated fatty acyl CoA is transported into the mitochondria Carnitine Carnitine 29 58  β -oxidation Acyl CoA Acyl CoA Dehydrogenase OXIDATION Trans-α,β-Enoyl-CoA Enoyl-CoA hydrase HYDRATION L-β-Hydroxyacyl-CoA L-β-Hydroxyl-CoA OXIDATION dehydrogenase β-Ketoacyl-CoA Thiolase CLEAVAGE Acyl CoA Acetyl CoA 59 Stoicheometry of Palmitate oxidation Palmitoyl-CoA + 7 FAD + 7 NAD+ + 7 CoA-SH + H2O 8 Acetyl-CoA + 7 FADH2 + 7 NADH + H+ 7NADH (ETC: 1 NADH= 2.5) 17.5 ATP 7FADH2 (ETC: 1FADH2 = 1.5) 10.5 ATP Sub-total 28ATP From 8 acetyl CoA oxidized in KREBS?TCA cycle: 3 NADH x 2.5 x 8 60 ATP 1 FADH2 x 1.5 x 8 12 ATP 1 GTP/ATP x 8 8 ATP Sub-total 80 ATP Total 28 = 80 = 108 Net ATP = 108 – 2 (ATP energy equivalent used to activate fatty acid) =106 ATP 30 60  Peroxisomal b-Oxidation Peroxisomes - organelles that carry out flavin- dependent oxidations, regenerating oxidized flavins by reaction with O2 to produce H2O2 Electrons go to O2 rather than e- transport chain. Fewer ATPs result. No requirement for carnitine to transport the fatty acyl CoA into the peroxisome. (it can diffuse through) Similar to mitochondrial β-oxidation, but initial double bond formation is by acyl-CoA oxidase The oxidation of fatty acid is incomplete. Long fatty acid chains are partially oxidized to form medium or short chain fatty acids. These short / medium acyl chains are linked to carnitine and brought into the mitochondria. http://www.slideshare.net/SaraHassan4/lysosomes-and-peroxisomes 61 Odd-carbon fatty acid  Odd-carbon fatty acids are metabolized Propionyl CoA normally, until the last three-C fragment - Propionyl CoA carboxylase propionyl-CoA - is reached. Biotin  Three reactions convert propionyl-CoA to succinyl-CoA. Note the involvement of biotin and B12 D-methymalonyl-CoA  Note pathway for net oxidation of succinyl-CoA Methylmalonyl CoA epimerase  Succinyl CoA cannot directly enter KREBS cycle. It is converted to malate then, transported to the cytosol. L-methylmalonyl CoA  There, it is oxidatively decarboxylated to Methylmalonyl pyruvate and CO2 by malic enzyme. CoA mutase B12  Pyruvate is transported back to the mitochondria, then completely oxidized via pyruvate dehydrogenase to acetyl CoA which then enters the TCA cycle. Succinyl CoA 31 62  Oxidation of unsaturated fatty acids Double bond at odd numbered carbon atom. O 9 C S CoA 3FADH2 + 3NADH + H+ + 3Acetyl-CoA O 3 C S CoA cis-∆3-enoyl-CoA Enoyl-CoA isomerase O C S CoA 2 trans-∆2-enoyl-CoA 63 Double bond at even numbered carbon atom. O C S CoA 8 2FADH2 + 2NADH + H+ O + 2Acetyl-CoA C S CoA 4 cis-∆4-enoyl-CoA Acyl-CoA dehydrogenase O C S CoA 4 2 trans-∆2-cis-∆4-dienoyl-CoA NADPH + H+ Dienoyl-CoA reductase O NADP+ 3 C S CoA trans-∆3-enoyl-CoA Enoyl-CoA isomerase O C S CoA 2 trans-∆2-enoyl-CoA 32 64  Regulation of Fatty Acid Oxidation Oxidation of fatty acids occur when energy levels are low. Malonyl-CoA carnitine acyltransferase I Enzymes of β-oxidation regulated by NADH Acyl-CoA dehydrogenase Acetyl-CoA thiolase 65 Impaired fatty acid oxidation Carnitine palmitoyltransferase I Affects only the liver, resulting in reduced fatty acid oxidation and ketogenesis with hypoglycemia Carnitine palmitoyltransferase II Affects primarily skeletal muscle (weakness, necrosis with myoglobinuria) Carnitine deficiency -preterm infants: owing to inadequate biosynthesis or renal leakage. - losses during haemodialysis Leads to increase in plasma free fatty acids, lipid accumulation in muscles and muscle weakness Ketoacidosis Results from prolonged ketoacidosis. Fatal in uncontrolled diabetes. Acyl CoA Dehydrogenase deficiency Sudden infant death syndrome (SIDS). Medium chain acyl CoA dehydrogenase (deficient in up to 10% of these infants) Imbalance in glucose and fatty acid oxidation 33 66  Ketone Bodies Ketone bodies (acetone, acetoacetate and b- hydroxybutyrate) are synthesized in the liver (mitochondrial matrix) when fat breakdown is predominant Major energy source for brain during starvation Source of fuel for brain, heart and muscle 67 Ketone Bodies (Synthesis) 1 2 Ketone Bodies 3 Acetoacetate D-β-Hydroxybutyrate Acetone 34 68  Ketone Bodies and Diabetes "Starvation of cells in the midst of plenty" Glucose is abundant in blood, but uptake by cells in muscle, liver, and adipose cells is low Cells, metabolically starved, turn to gluconeogenesis and fat/protein catabolism In type I diabetics, OAA is low, due to excess gluconeogenesis, so Acetyl-CoA from fat/protein catabolism does not go to TCA, but rather to ketone body production Acetone can be detected on breath of type I diabetics 69 OH Utilization of - OOC CH2 CH CH3 acetoacetate D-3-Hydroxybutyrate + NAD hydroxybutyrate  Brain uses acetoacetate during dehydrogenase NADH + H + starvation. O  Heart muscle and renal cortex - OOC CH2 C CH3 prefer to use acetoacetate as Acetoacetate source of energy compared to Succinyl-CoA glucose. CoA transferase  Liver has no CoA transferase. Succinate O O  Concentration of ketone bodies; normal: 0.2 mM; CH3 C CH2 C S CoA starvation: 3-5 mM; Acetoacetyl-CoA diabetes (ketoacidosis): ~20 mM CoASH Ketothiolase O 2 CH3 C S CoA Acetyl-CoA 35 70  Cholesterol Biosynthesis 71 Key Principles of Cholesterol -  Biosynthesis, rather than diet, contributes the majority of body cholesterol, which can deposit in artery walls to cause atherosclerosis.  Statin drugs can be used to curtail synthesis, whereas intake of unsaturated fatty acids improves cholesterol clearance.  Note: Cholesterol is only excreted from the body in the form of bile 36 72  Cell membrane structure bile acid General steroid synthesis Functions of hormone synthesis Cholesterol Vitamin D synthesis 73 Synthesis of HMG-CoA in mitochondria and cytoplasm CYTOSOL MITOCHONDRION HMG CoA reductase STARVATION FED STATE STATE 37 74  The four stages of Stage 1 Acetyl CoA (C2) cholesterol biosynthesis  rate-determining step HMG-CoA  feedback inhibited by cholesterol NADPH  amount controlled by HMG-CoA induction/repression NADP+ Reductase  hormonally controlled via Mevalonate (C6) phosphorylation Stage 4 Lanosterol (C30) Stage 2 Stage 3 Mevalonate O2 Squalene (C30) (19 steps) 3ATP NADPH CO2 O2 Cyclization 3ADP Active Isoprenoids (C5) NADPH Squalene NADP+ 3 CH3 Several epoxidase/ NADPH Condensation Steps NADP+ cyclase Cholesterol (C27) NADP+ Lanosterol (C30) Squalene (C30) (4-ring structure) 75 Notes on Cholesterol Biosynthesis Carbons for cholesterol are carried from the mitochondrion to the cytoplasm via citrate, which is cleaved by citrate lyase to acetyl CoA HMG-CoA is produced in the cytoplasm from acetyl CoA via HMG-CoA synthase HMG-CoA is reduced, using NADPH, to mevalonate by HMG-CoA reductase, the rate- limiting, regulated step of cholesterol synthesis; HMG-CoA reductase is competitively inhibited by statins, drugs which lower cholesterol. Mevalonate is phosphorylated (using ATP) to 5-carbon active isoprenoids, capable of polymerization and reduction (with NADPH) to form the linear squalene molecule (C30) Squalene is cyclized, oxidized (O2) and reduced (NADPH) to lanosterol (C30) in a reaction catalyzed by squalene epoxidase/cyclase Lanosterol is oxidized (O2) and reduced (NADPH) to cholesterol (C27) with the loss of 3 carbons HMG-CoA reductase is the rate-limiting, regulated step of cholesterol synthesis; it is competitively inhibited by statins, drugs which lower cholesterol. HMG-CoA reductase is also inactivated by phosphorylation (glucagon triggers in starvation), and inactivated by proteolysis in the presence of excess cholesterol Squalene is cyclized, oxidized (O2) and reduced (NADPH) to lanosterol (C30) in a reaction catalyzed by squalene epoxidase/cyclase 38 76  BILE ACID SYNTHESIS SEVERAL STEPS 77 CIRCULATION OF BILE ACIDS 39 78  Steroid hormone synthesis in adrenal cortex http://www.slideserve.com/helene/steroid-hormone-synthesis-in-adrenal-cortex 79 Task 14 Compare the steps involved in the synthesis (starting from acetyl CoA) and beta oxidation of palmitic acid. You may tabulate your points. Task 15 Discuss the importance of ketone body formation in the liver. 40 80 Discuss the importance of ketone body formation in the liver. Ketone body formation (ketogenesis) in the liver is a crucial metabolic process, especially during periods when glucose availability is low, such as fasting 1. Alternative Energy Source -Ketone bodies (mainly beta-hydroxybutyrate and acetoacetate) are water-soluble molecules derived from fatty acids. -They serve as an alternative energy source for tissues that cannot directly utilize fatty acids, such as the brain, muscles, and heart, especially during glucose scarcity. -During prolonged fasting, ketone bodies can supply up to 75% of the brain s energy needs, sparing muscle protein from being broken down for gluconeogenesis. 2. Preservation of Muscle Protein -Without sufficient glucose, the body would need to break down muscle protein for gluconeogenesis (glucose production) to maintain blood sugar levels. -Ketogenesis helps reduce the demand for gluconeogenesis by providing a substitute fuel for various tissues, thus preserving muscle protein. 3. Efficient Utilization of Fat Stores -Ketogenesis allows for the mobilization of fatty acids from adipose tissue to be converted into ketone bodies, making fat a highly efficient fuel source. -This process enables the body to survive on stored fat for extended periods, even when dietary energy intake is low. 4. Maintenance of Blood Glucose Levels -By shifting the fuel supply from glucose to ketones for certain tissues, ketogenesis reduces the body s reliance on glucose. -This conserves blood glucose for tissues that are entirely dependent on it, such as red blood cells, helping maintain blood glucose levels within a critical range. 5. Role in Diabetes and Ketosis -In uncontrolled diabetes type 1, excessive ketone body formation can lead to diabetic ketoacidosis (DKA), a dangerous condition where ketone levels rise too high and cause acidosis. -However, in controlled amounts, ketone bodies can serve as a valuable energy source and may have therapeutic potential in conditions like epilepsy, Alzheimer s disease, and other neurological disorders. 6. Hormonal Regulation and Metabolic Adaptation -Ketone body production is regulated by insulin and glucagon. When insulin levels are low, such as in fasting, glucagon promotes ketogenesis. -This adaptive response enables the body to switch to fat metabolism, supporting energy needs during periods of low carbohydrate intake. In summary, ketone body formation in the liver provides essential metabolic flexibility, allowing the body to maintain energy homeostasis and protect critical tissues during periods of carbohydrate scarcity ’ ’ ’ 1. Energy Source -Lipids provide more than twice as many calories per gram as carbohydrates and proteins. Kids have high energy needs to support their growth, development, and daily activities, and fats are a key source of this energy. 2. Brain Development -Fats are crucial for brain growth and function, as the brain is composed largely of fat. Essential fatty acids (such as DHA and ALA, omega-3s, and omega-6s) are particularly important for the development of the brain, nervous system 3. Absorption of Fat-Soluble Vitamins -Certain vitamins, like vitamins A, D, E, and K, are fat-soluble, meaning they need dietary fat to be absorbed by the body. These vitamins are essential for immune support, bone health, and cell protection. 4. Hormone Production and Regulation -Lipids play a role in the production of hormones for growth and puberty. They also help regulate processes like inflammation and immune response. 5. Insulation and Protection Fats help insulate the body and maintain body temperature. They also provide a protective layer around organs, helping cushion and protect them from injury. 6. Building Blocks of Cells -Lipids are fundamental components of cell membranes, which are necessary for every cell in the body. This is especially important in growing children, who are constantly producing new cells. 7. Satiation and Healthy Eating Patterns -Healthy fats in the diet help kids feel fuller for longer, which can prevent overeating and help maintain a balanced diet. Including healthy fats can also establish positive eating habits and support balanced nutrition in the long term. 1. Nonpolar Nature: -Lipid molecules are primarily composed of long chains of carbon and hydrogen atoms, forming nonpolar bonds. Since water is a polar molecule, it does not interact well with nonpolar substances like lipids. As a result, lipids do not dissolve in water.(hydrophobic) 2. Lack of Affinity for Water: -Water molecules are strongly attracted to each other due to hydrogen bonding, and they tend to exclude nonpolar molecules. This exclusion causes lipids to separate from water, forming a barrier that water cannot easily pass through. 3. Formation of Protective Barriers: -The hydrophobic nature of lipids makes them ideal for creating waterproof barriers, such as the cell membrane s lipid bilayer and protective coatings (like waxes on plant leaves or animal fur). These barriers prevent water from passing through easily, helping organisms retain moisture and protect against external water. 1. Energy Sources -Fats provide a dense source of energy, delivering 9 calories per gram, which is more than double the energy provided by carbohydrates or proteins. This is particularly valuable for sustaining energy levels throughout the day. 2. Supports Brain Health -Fats, especially essential fatty acids like omega-3s and omega-6s, are crucial for brain health. They support cognitive function, mood regulation, and overall brain development and maintenance, especially in children and during pregnancy. 3. Absorption of Fat-Soluble Vitamins -Vitamins A, D, E, and K are fat-soluble, meaning they require fat for proper absorption and transportation in the body. These vitamins are essential for immune function, bone health, blood clotting, and protecting cells from oxidative damage. 4. Hormone Production and Regulation -Fats are necessary for the production of hormones, including sex hormones like estrogen and testosterone, as well as hormones involved in growth and metabolism. A balanced intake of healthy fats helps maintain hormonal balance. 5. Cell Structure and Function -Fats are key components of cell membranes. The lipid bilayer in cell membranes regulates what enters and exits cells, helping maintain proper cell function. This structural role is fundamental for every cell in the body. 6. Protection and Insulation -Dietary fats help protect vital organs by cushioning them. Fats also provide insulation, helping the body maintain its temperature by conserving heat. 7. Satiety and Flavor -Fats help increase satiety, meaning they keep you feeling full longer, which can prevent overeating. They also add flavor and texture to foods, making meals more enjoyable. 8. Essential Fatty Acids -Certain fatty acids, like omega-3 and omega-6, are “essential,” meaning the body cannot produce them on its own and must obtain them from food. These fatty acids support heart health, reduce inflammation, and play a role in brain function. ’