Transcript Slide 1
1 Lipids and lipoproteins metabolism 2 Outline 1. Introduction 2. Digestion and absorption in GI 3. Formation and secretion of lipoproteins (chylomicron) by enterocytes 4. Blood circulation and targeting of dietary lipids and lipoproteins 5. Destination of fatty acids in tissues 6. Lipid transport in fed state 7. Lipid transport in fasted state 8. Oxidation of fatty acids 3 1. Importance of lipids and lipoproteins • • • • • • • Heterogeneous group of water insoluble organic molecules Major source of energy (9Kc/1gr) Storage of energy (TAG in adipose tissue) Amphipatic barriers (PL, FC) Regulatory or coenzyme role (vitamins) Control of body’s homeostasis (steroid hormones, PG) Consequences of imbalance in lipids and lipoproteins metabolism: – Atherosclerosis – Obesity – Diabetes 4 1. Importance of lipids and lipoproteins Obesity Atherosclerosis 5 Lipid metabolism 2. Digestion and absorption of Dietary fats in GI 6 2.1. Dietary fats contents • Triacylglycerol (TAG) – Over 93% of the fat that is consumed in the diet is in the form of triglycerides (TG) or TAG • Cholesterol (FC, CE) • Phospholipids (PL) • Free fatty acids (FFA) 7 2.2. Dietary sources of Lipids • Animal Sources • Vegetable Sources 8 General schematic 9 2.3. Digestion of dietary fats Digestion in stomach Lingual lipase -----acid stable Gastric lipase -----acid stable • These enzymes are most effective for short and medium chain fatty acids • Milk, egg yolk and fats containing short chain fatty acids are suitable substrates for its action • Play important role in lipid digestion in neonates 10 2.4.Digestion in small intestine 11 2.5. Bile Salts Bile salts are synthesized in the liver and stored in the gallbladder They are derivatives of cholesterol Bile salts help in the emulsification of fats Bile salts help in combination of lipase with two molecules of a small protein called as Colipase. This combination enhances the lipase activity 12 2.6. Pancreatic enzymes in degradation of dietary lipids • Pancreatic Lipase (along with colipase) – Degradation of TAG • Cholesteryl estrase – Degradation of cholesteryl esters • Phospholipase A2 and lysophospholipase - Degradation of Phospholipids 13 2.6. Pancreatic enzyme PLase A2 14 2.7. Control of lipid digestion Cholecystokinin Secretin Bicarbonate 15 2.8. Disorders 1. Lithiasis 2. Cystic fibrosis 16 2.8. Disorders: Lipid Malabsorption • Steatorrhea: increased lipid and fat soluble vitamin excretion in feces. – Possible causes of steatorrehea • Colipase deficiency 17 3. Absorption and secretion of lipids by enterocytes TAG: triacylglycerol DAG: diacylglycerol MAG: monoacylglycerol FA: fatty acid CL: cholesterol BS: bile salt LPA: lysophosphatidate CE: cholestryl ester ACAT: acyl-CoA cholesterol acyl transferase CM: chylomicron MTP: microsomal TAG transfer protein AGPAT: 1-acylglycerol-3-phosphate-O-acyltransferase 18 3. Secretion of lipids from enterocytes After a lipid rich meal, lymph is called chyle 19 4. Blood circulation and targeting of dietary lipids and lipoproteins 20 4. Blood circulation and targeting of lipids and lipoproteins 21 4.1. ApoC-II, lipoprotein lipase (LPL) , deficiency and heparan sulfate Glycerol (exogenous) Chylomicron remnant Clearing factor LPL Liver HDL 22 6. Destination of fatty acids in tissues • Muscle tissue and liver: Catabolism (oxidation) – The end product of FAs catabolism (acetyl-CoA): • as fuels for energy production (TCA) • as substrates for cholesterol and ketone body synthesis • Adipose tissue: Storage (TAG) 23 7. Lipids and lipopoteins transport in fed state Small intestine Dietary TAG Blood stream liver Glucose & other fuels Acetyl-CoA FAs TAG Chylomicron (TAGendo) and VLDL (TAGexo) Adipose tissue FAs FAs Muscle energy TAGs 24 8. Lipids and lipopoteins transport in long Brain fasted state liver Ketone bodies FAs Glucose Acetyl-CoA Acetyl-CoA Glycerol energy Ketone bodies Blood stream ketone bodies FAs-albumin glycerol Adipose tissue FAs+Glycerol FAs(+ketone bodies) Muscle energy TAGs 25 26 • Pathway for catabolism of saturated fatty acids at the β carbon atom with successive removal of two carbon atoms as acetyl CoA • Site: – Cytosol (activation) – Mitochondria • Membrane transport • Matrix ( β oxidation) 27 9.1.1. Activation and transport of fatty acids into mitochondria Acyl CoA synthase 28 9.1.1. Entry of short and medium chain FA into mitochondria • Carnitine and CAT system not required for fatty acids shorter than 12 carbon length. • They are activated to their CoA form inside mitochondrial matrix. 29 9.1.1.1. Carnitine deficiencies • Primary causes: – Carnitine acyl transferase-I (CAT-I) deficiency: mainly affects liver – Carnitine acyl transferase-II (CAT-II) deficiency: mainly affects skeletal and cardiac muscles. • Secondary causes : – liver diseases: decreased endogenous synthesis 30 9.1.1.1. Consequence of carnitine deficiencies • Excessive lipid accumulation occurs in muscle, heart, and liver • Cardiac and skeletal myopathy • Hepatomegaly • Low blood glucose in fasted state hypoglycemia coma 31 32 • Provision of energy – Major pathway of acetyl-CoA • Cholesterol production • Ketone bodies production – Diabetes – Starvation 33 Types of fatty acyl CoA dehydrogenases • Long chain fatty acyl CoA dehydrogenase (LCAD) • Medium chain fatty acyl CoA dehydrogenase (MCAD) • Short chain fatty acyl CoA dehydrogenase (SCAD) MCAD deficiency is thought to be one of the most common inborn errors of metabolism. 34 Muscle tissue and liver The first level Insulin TAG Glucagon Epinephrine The second level The third level - + FFA FFA CAT 1 FFA Acetyl-CoA NADH Adipose tissue TCA Malonyl-CoA Acetyl-CoA and NADH inhibition of ᵦ oxidation enzymes 35 Peroxisomal FA oxidation • Acts on very long chain fatty acids (VLCFAs) • Zellweger syndrome – Absence of peroxisomes – Rare inherited disorder – VLCFA cannot be oxidized – Accumulation of VLCFA in brain, blood and other tissues like liver and kidney 36 Omega oxidation • It is a minor pathway • Takes place in microsomes • Involves oxidation of last carbon atom ( ω carbon) • More common with medium chain fatty acids 37 Alpha oxidation • Seen in branched chain fatty acid, phytanic acid • Occurs in endoplasmic reticulum • Refsum disease – Genetic disorder – Caused by a deficiency of alpha hydroxylase – There is accumulation of phytanic acid in the plasma and tissues. – The symptoms are mainly neurological. 38 Acetyl CoA and lipid metabolism Mitochondria Cytosol GLC Protein Ketone bodies HMG-CoA TCA FA TAG & PL Acetyl-CoA HMG-CoA TAG - Protein -Glucose Cholesterol Pentose phosphate pathway 39 De Novo synthesis of fatty acids • Saturated fatty acids are synthesized from acetyl CoA • Occurs in cytoplasm • Occurs mainly in liver, adipose tissue and lactating mammary gland • Need to – acetyl CoA – NADPH 40 De Novo synthesis of fatty acids • Phase I – Transport of substrates into cytosol – Carboxylation of acetyl-CoA to malonyl-CoA • Phase II – Utilization of substrate to form palmitate by fatty acid synthase complex • Phase III – Elongation and desaturation of palmitate to generate different fatty acids 41 Acetyl CoA activation and regulation of it + Glucagon and epinephrine 42 Synthesis of palmitate by fatty acid synthase(FAS) 43 Modification of dietary and endogenous fatty acids • Chain elongation to give longer fatty acids • Desaturation, giving unsaturated fatty acids 44 Modification of dietary and Essential fatty acids endogenous fatty acids ω-3 ω-6 ω-7 ω-9 45 TAG formation Glucose Glycerol ATP ADP NADH, H+ NAD+ Pyruvate Dihydroxy acetone phosphate Acyl-CoA CoA Glycerol 3-P Acyl-CoA NADH, H+ NAD+ 1acyl-dihydroxy acetone phosphate CoA 1acyl- glycerol 3-P Acyl-CoA CoA 1,2Diacyl- glycerol 3-P (phosphatidate) Pi Monoacylglycerol Acyl-CoA CoA 46 Diacylglycerol Acyl-CoA CoA TAG Fates of TAG in liver and adipose tissue • Adipose tissue: TAG stored in cytosol • Liver: very little stored. Exported out of liver in VLDL , which exports endogenous lipids to peripheral tissues 47 FFA Lipolysis 48 Mobilization of stored fats and release of FAs Glucagon & epinephrine + P P P P P P HSL HSL-P 49 Metabolism of cholesterol 50 Cholesterol 51 Cholesterol importance • • • • • Membrane component Steroid synthesis Bile acid/salt precursor Vitamin D precursor It is synthesized in many tissues from acetyl-CoA and is eliminated from the body in the bile salts 52 Liver cholesterol pool De novo synthesis Diet Cholesterol synthesized in extrahepatic tissues Liver cholesterol pool Secretion of HDL and VLDL Free cholesterol Conversion to bile salts/acid In bile 53 Cholesterol Synthesis • Occurs in cytosol • Requires NADPH and ATP • All carbons from acetyl-CoA • Highly regulated • Site : Liver, adrenal cortex, testis, ovaries And intestine. • All nucleated cells can synthesize cholesterol. • Area :The enzymes of synthesis are located partly in endoplasmic reticulum and partly in cytoplasm. 54 Cholesterol Synthesis 55 Regulation of Cholesterol synthesis Covalent modification 56 Regulation of Cholesterol synthesis • Regulation at transcription 57 Lipoprotein metabolism 58 Structure of lipoprotein INTEGRAL APOPROTEINS CHOLESTEROL ESTERS MONOLAYER OF PHOSPHOLIPID AND CHOLESTEROL CORE TRIGLYCERIDES PERIPHERAL APOPROTEIN 59 Apoproteins A A-I Liver& intestine A-II Liver B B-48 B-100 Intestine Liver C E C-l C-ll C-lll Liver All Liver 60 Classification Based on density by ultracentrifugation i. ii. iii. iv. v. Chylomicrons Very Low Density Lipoprotein Intermediate Density Lipoprotein Low Density Lipoprotein High Density Lipoprotein 61 Composition and size of lipoprotein 62 Lipoprotein function 63 Exogenous cycle(Metabolism of CM) 64 Endogenous cycle(VLDL) 65 HDL- cholestrol metabolism reverse cholesterol transport and LDL metabolism 66 • Regulated: by LDL receptor • Unregulated : by scavenger receptor(SR) 67 Regulated: by LDL receptor 68 regulated LDL uptake by LDL receptor 69 Unregulated LDL uptake by scavenger receptor Antioxidants - + Free radicals Scavenger receptor Atherosclerosis 70 Atherosclerosis • Atherosclerosis is a form of arteriosclerosis in which thickening and hardening of the vessel are caused by the accumulation of lipid-laden macrophages or foam cell within the arterial wall, which leads to the formation of a lesion called a plaque • Atherosclerosis is not a single disease • It is the leading contributor to coronary artery and cerebrovascular disease 71 Atherosclerosis 72 Hypercholesterolemia • Normal serum cholesterol level 150-200mg/dl • Increased cholesterol level is seen in following conditions diabets mellitus, lipid nephrosis, hypothyroidism • Atherosclerosis • Xanthomas (deposition of cholesterol in subcutaneous tissue) • Corneal arcus (deposits of lipid in cornea) 73 Fredrickson classification of the hyperlipidemias 74 Degradation of Cholesterol • Synthesis of bile acids Excretion in the feces 75 76 Cholesterol-lowering drugs • • • • • Statins Fibric acid derivatives Niacin Bile-acid resins Cholesterol absorption inhibitors 77 Ketone bodies 78 Ketone bodies • Ketone bodies are metabolic products that are produced in excess during excessive breakdown of fatty acids Acetone βhydroxybutyrate Acetoacetate 79 Ketone bodies importance • Alternate sources to glucose for energy • Production of ketone bodies under conditions of cellular energy deprivation • Utilization of ketone bodies by the brain 80 ketone bodies production and utilization HMG-CoA synthase 81 • By availability of acetyl CoA • Level 1 – Lipolysis • Level 2 – Entry of fatty acid to mitochondria • Level 3 – Oxidation of acetyl CoA 82 83 Diabetic Ketoacidosis With each ketone body, one hydrogen atom is released in bloodlowering of pH Acidosis. 84 Metabolism of complex lipids Phospholipids • • • • • Polar, ionic compounds alcohol Phosphodiester bridge Diacylglycerol or Sphingosine Types: – Glycerophospholipids – Sphingophospholipids (sphingosine) 85 Synthesis of phospholipids • Synthesized in smooth endoplasmic reticulum. • Transferred to Golgi apparatus • Move to membranes of organelles or to the plasma membrane or released out via exocytosis • All cells except mature erythrocytes can synthesize phospholipids 86 Synthesis of Glycerophospholipids • Biosynthesis of anionic Glycerophospholipids – Phosphatidylglycerol(PG) – Phosphatidylinositol(PI) – Cardiolipin • Biosynthesis of neutral glycerophospholipids – Phosphatidylcholine(PC) – Phosphatidylethanolamine(PE) • 87 Synthesis of Glycerophospholipids • First strategy: • biosynthesis of anionic Glycerophospholipids – CTP:phosphatidate citidyl transferase: R1 R2 R1 CTP PPi R2 OP Phosphatidate Alcohol CMP R1 R2 CDP CDP-DAG phosphoalcohol Phosphatidyl alcohol 88 Synthesis of Glycerophospholipids • Second strategy: • Biosynthesis of neutral glycerophospholipids – CTP:phospho alcohol citidyl transferase: Alcohol Phosphoalcohol CDP-alcohol CMP R1 R2 R1 R2 OH DAG phosphoalcohol Phosphatidyl alcohol 89 Sphingophospholipids 90 Sphingomyelin synthesis • Ceramide is required for sphingomyelin synthesis PC DAG 91 Degradation of glycerophospholipids • Phospholipases remove one fatty acid from C1 or C2 and form lysophosphoglyceride. • Lysophospholipases act upon lysophosphoglycerides. – – – – Phospholipase A1 Phospholipase A2 Phospholipase C Phospholipase D 92 Phospholipases Phospholipse Product Significant A1 FA--- 1-lysophospholipid Phospholipid transformation A2 FA--- 2-lysophospholipid Phospholipid transformation, Eicosanoid synthesis B FA---- Glycerol 3-phosphoalcohol Lysophospholipid degradation C Phosphoalcohol---1,2DAG Secondary messenger production D Alcohol---- phosphatidic acid Secondary messenger production 93 Degradation of Sphingomyelin • Sphingomyelinase • Ceramidase • Sphingosine and ceramide act as intracellular messengers. 94 Glycolipids • Carbohydrate and lipid components • Derivatives of ceramide • Essential components of all membranes, greatest amount in nerve tissue • Interact with the extracellular environment • No phospholipid but oligo or mono-saccharide attached to ceramide by O-glycosidic bond. 95 Classes of Glycosphingolipids • Neutral glycosphingolipids : – Cerebrosides – Globosides • Acidic glycosphingolipids: – Ganglioside – Sulfatides 96 Synthesis of Neutral Glycosphingolipids • Site: – Golgi apparatus • Subtrates – Ceramide, sugar activated by UDP • Galactocerobrosides – Ceramide + UDP- galactose • Glucocerebrosides – Ceramide + UDP – glucose • Enzymes – Glycosyl transferases 97 Synthesis of Acidic Glycosphingolipids • Gangliosides – ceramide + two or more UDP- sugars react together to form Globoside. – NANA combines with globoside to form Ganglioside. 98 Synthesis of Acidic Glycosphingolipids • Sulfatides – galactocerebroside gets a sulphate group from a sulphate carrier with the help of sulfotransferase and forms a sulfatide. 99 Degradation of glycosphingolipids • Done by lysosomal enzymes • Different enzymes act on specific bonds hydrolytically ---- the groups added last are acted first. 100 Sphingolipidoses • • • • Lipid storage diseases Accumulation of sphingolipids in lysosomes Partial or total absence of a specific hydrolase Autosomal recessive disorders 101 Degradation of glycosphingolipids 102 Eicosanoids- Classification Eicosanoids are classified in to two main groups1) Prostanoids 2) Leukotrienes and Lipoxins Prostanoids are further sub classified in to three groupsa) Prostaglandins(PGs) b) Prostacyclins(PGIs) c) Thromboxanes (TXs) 103 Characteristic features of prostaglandins 1) 2) 3) 4) Act as local hormones Show the autocrine and Paracrine effects Are not stored in the body Have a very short life span and are destroyed within seconds or few minutes 5) Production increases or decreases in response to diverse stimuli or drugs 6) Are very potent in action. Even in minute (ng concentration), biological effects are observed. 104 Synthesis of eicosanoids • Linoleic acid is the dietary precursor of PGs. • Arachidonic acid is formed by elongation and desaturation of linoleic acid. • Membrane bound phospholipids contain arachidonic acid. • Phospholipase A2 causes the release of arachidonic acid from membrane phospholipids. 105 Synthesis of eicosanoids NSAIDs Steroidic antiinflammation drugs 106