lipid metabolism

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Slide 1:

Lipid Metabolism by Dr. Mahmoud A Abdelwahab Lecturer of Medical Biochemistry

Slide 2:

Lipid Digestion Processing of dietary lipids Emulsification of dietary lipids Enzymatic hydrolysis Hormonal Control Absorption of lipids by enterocytes Re-synthesis of TAG & cholesterol esters Secretion of lipids from enterocytes

Slide 3:

Gastric processing of lipids (Action of Relatively Acid Stable Lipases) Ebner’s glands  lingual lipase Gastric mucosal cells  gastric lipase Both are relatively acid stable (RAS) act at (pH 4 – 6) & named Acid lipases In neonates, for whom milk fat is the primary caloric source. In cystic fibrosis patients who are suffering of deficient pancreatic lipase

Slide 4:

Cystic fibrosis ( CF ) Autosomal Recessive Disease Mutation of CFTR gene ( CF Trans-membrane Conductance Regulator)  chloride secretion + Cl - in sweet ( Sweet Test) In pancreas, hydration  viscosity of pancreatic enzymes  stasis  pancreatic enz. deficiency  steatorrhoea (Loss of lipids in stool). Clinical Condition

Slide 5:

Intestinal processing of lipids

Slide 6:

LPL 2- MAG PL TAG 1- MAG Glycerylphosphoryl- base CE Chol. + FA Glycerol + FA

Slide 7:

Control of lipid digestion

Slide 8:

Absorption of lipids by Enterocytes Short and medium chain FA as well as glycerol are taken by enterocytes without aid of mixed micelles. It is important in cases of malabsorption to give short chain FA as dietary therapy.

Re-synthesis & Secretion of TAG & CE:

Re-synthesis & Secretion of TAG & CE Brush border Absorbed FA Thiokinase COASH Acyl CoA ATP ER 2- MAG Cholesterol Acyl transferases TG CE Apo B 48 PL

Slide 10:

Obstructive biliary canals  loss of emulsification of lipids + loss of activation of lipases Jaundice + Steatorrhoea + Vitamin Deficiencies. Clinical Implications In cystic fibrosis, chronic pancreatitis or obstructive pancreatic duct  Steatorrhoea. Ezetimibe , a drug further reduce cholesterol absorption by enterocytes. Orlistat , a drug used in ttt of obesity is an inhibitor of pancreatic lipase and colipase. Any cause of steatorrhoea  bulky, greasy and offensive stool. Digestion and absorption of all elements of chime will be affected due to coating effect of fat

Slide 11:

Fate of Absorbed lipids by tissues Chylomicron Apo C-II Lipase TG FFA + Glycerol Glycerol 3-phosphate DHAP

Slide 12:

Clinical Condition Type I Hyperlipoproteinemia Deficiency of lipoprotein lipase Rare familial, Autosomal Recessive disorder Manifested by Fasting Chylomicrons & TG N.B. FFA are circulating bound to Albumin to reach the tissues. Nephrotic Syndrome : Disease ch . ch . by loss of urinary albumin ( Albuminuria  HypoAlbuminemia ). The condition is associated with increased TG and cholesterol & Lipiduria .

Slide 14:

Fate of absorbed lipids

Slide 15:

Metabolism of glycerol Phospholipids Glucose Reversal of glycolysis

Slide 16:

Depot Fat (Variable element) Metabolism

Slide 17:

Lipogenesis A process of esterification between Acyl (FA) residues and active Glycerol Fatty acid Glycerol Sources Active acetate (Acetyl CoA) Plasma FFA Glucose Free glycerol in liver, kidneys & intestine. Enzymes FA synthase Plasma LP-Lipase Glycolysis Glycerol kinase Yield Acyl CoA Glycerol -3-P Regulator Enzymes FAS low activity in adipocytes Insulin on adipocytes Deficient GK in adipose

Slide 18:

Lipolysis Hydrolysis of TAG by Hormone Sensitive Lipase (HSL)  Monoacylglycerol ( hydrolyzed by MAG lipase)  Glycerol + FFA Regulation of Lipolysis

Slide 19:

Lipase Phosphatase Active protein Kinase A Inactive protein Kinase A ATP Adenylate Cyclase 5’- AMP Phosphodiesterase

Slide 20:

Lipolysis versus lipogenesis in adipose tissue

Slide 21:

Fatty Acid Oxidation

Fatty acid oxidation:

Fatty acid oxidation Mitochondrial Peroxisomal FA chain < C20 . End product either acetyl CoA ( β Ox) or Propionyl CoA ( α Ox) or C6 Adipic & C8 Suberic ( ω Ox) Dehydrogenase steps give no H2O2. Importance Energy , Prevent accumulation of toxic FA & Production of cerbrosides. More specific for long chain FA End product is Octanyl – CoA (further metabolized by Beta-oxidation in the mitochondria) . First DH step  H2O2. Importance Needed to  bile acid & Plasmalogen synthesis

Fatty acid oxidation:

Fatty acid oxidation Mitochondrial

Slide 25:

Mitochondrial FAO

Slide 26:

Beta Oxidation of Fatty Acids

Slide 27:

Step 1: Activation of FA by CoA-SH Fatty acids are activated by attaching CoA : Occurs on the cytoplastic face of the outer mitochondrial membrane. Catalyzed by acyl CoA synthetase. The reaction is irreversible . 2 ATP are used in this activation step .

Slide 28:

Step 2: Transport of Acyl CoA into mitochondria: Inner mitochondrial membrane is impermeable to long chain acyl CoA molecules so a Carnitine transport system is required .

Slide 29:

Carnitine β Hydroxy, γ - trimethyl ammonium Butyrate (CH 3 ) 3 .N + .CH 2 .CH(HO).CH 2 .COOH Particularly abundant in muscles , which contains ~ 97 % of whole endogenous carnitine. Synthesized in liver from Lysine (K) & Methionine (M) Along with fructose it plays its role as source of energy for sperms. Carnitine Shuffle Shuttle Transporting System: Is formed of CAT-I Binder, CACT Translocator & CAT-II Splitter

Slide 30:

Step 3: Oxidation of Acyl CoA: A A (USA-CoA)

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Slide 33:

Back To Start D

Slide 34:

Mitochondria Beta – Oxidation of FA

Slide 37:

Deficiency of vitamin B 12  L-Methyl Malonyl Aciduria

Slide 38:

Accumulation of Polyenoic A Zellweger’s Neurodisorder

Slide 39:

Defective Carnitine Transporting System

Slide 40:

Defective Acyl CoA Deficiencies Autosomal Recessive Most common FAO inborn errors ttt by CHO-rich diet Inherited Acute fatty liver in pregnancy Akee tree Jamaican Hypoglycin ttt by MCFA

Slide 42:

Ketogenesis & Ketolysis

Slide 43:

Ketone bodies spare glucose in prolonged fasting ( Starvation ). They are soluble in aqueous solution Ketogenesis occurs in the liver on increase both NADH+H & Acetyl CoA in the mitochondria . The rate limiting enzyme of Ketogenesis is HMG CoA synthase in liver only. They are utilized by all cells except liver cells which lacks thiophorase . Hepatic Mitochondrial condensation of Acetyl CoA

Slide 44:

Under most conditions (except long-term starvation) there are insufficient amounts of ketones available as a fuel . However, if glucose, ketones and fatty acids are all available, ketones become the preferred fuel . The primary tissues using ketones , when available, are brain, muscle, kidney and intestine, but not the liver

Slide 45:

Normal prevention of ketosis & events of ketosis .

Slide 46:

Ketosis ttt of ketosis: Glucose + K + HCO 3 + Insulin ± fluids . Insulin prevents increased ketogenesis by decreasing the rate of lipolysis and decrease FFA. Associated Hypokalaemia (due to insulin deficiency) is the cause of death in ketosis as well as ketoacidosis. Increased FA oxidation leads to increased ketogenesis . - Increased acetoacetate and hydroxybutyrate > 1 mg/dl in blood (Ketonaemia). Increased K.B. in urine is termed(Ketonuria). It is due to increase of ketogenesis that exceeding the balancing rate of ketolysis.

Slide 47:

Insulin cAMP HS Lipase PKA Phosphodiesterase activity Lipolysis FFA & Glycerol CHO Pyruvate & Oxaloacetate Acetyl CoA oxidation Liver Ketones Glucose Adipocyte

Slide 48:

CHO Pyruvate & Oxaloacetate Acetyl CoA oxidation Liver Ketones Ketone Bodies ATP + CO2 + H2O Succinyl CoA Acetyl CoA Oxaloacetate TCA TCA Extra-hepatic

Slide 49:

Cholesterol Synthesis & Catabolism

Slide 50:

HMG-CoA is formed by condensation of acetyl-CoA & acetoacetyl-CoA, catalyzed by HMG-CoA Synthase . HMG-CoA Reductase catalyzes production of mevalonate from HMG-CoA.

Slide 51:

The carboxyl of HMG that is in ester linkage to the CoA thiol is reduced to an aldehyde , and then to an alcohol . NADPH serves as reductant in the 2-step reaction. Mevaldehyde is thought to be an active site intermediate, following the first reduction and release of CoA.

Slide 52:


Slide 53:

C 30 C 10 C 15 C 27 3 CH3

Slide 55:

Cholesterol Catabolism & Bile Salts formation Deoxycholic & Lithocholic Reduction

Slide 57:

Regulation of Cholesterol Synthesis

Slide 58:

Regulation of cholesterol synthesis HMG- CoA Reductase , the rate-limiting step on the pathway for synthesis of cholesterol, is a major control point. (Activity affected by Covalent Modification): HMG-CoA Reductase activity is inhibited by phosphorylation , catalyzed by c AMP -Dependent Protein Kinase ( phosphorylated reductase is inactive ). The reverse occurs to activate the key enzymes by phosphoprotein phosphatase ( dephosphorylated reductase is active ) .

Slide 59:

Allosteric regulation of HMG- CoA Reductase HMG- CoA Reductase is allosterically inhibited by cholesterol, oxidized derivatives of cholesterol, mevalonate , & farnesol (dephosphorylated farnesyl pyrophosphate). Proteosomal regulation of HMG- CoA Reductase HMG- CoA Reductase includes a trans-membrane sterol-sensing domain that has a role in activating degradation of the enzyme via the proteosome.

Slide 60:

Regulated transcription : SREBP (sterol regulatory element binding proteins), is a family of transcription factors that regulate synthesis of cholesterol and fatty acids. When sterol levels are low , SREBP-2 is released from endoplasmic reticulum. SREBP-2 activates transcription of genes for HMG-CoA Reductase and other enzymes of the pathway for cholesterol synthesis.

Slide 61:

Drugs: Statin drugs, such as lovastatin ( Mevacor ) and derivatives (e.g., Zocor ) and Lipitor, are competitive inhibitors of HMG- CoA reductase , as they are structural analogs of mevalonate . Sitosterol & Ezitimibe decrease absorption of cholesterol. Cholestyramine binds the bile salts and minimizes entero-hepatic re-absorption of cholesterol. Lopid ( Gimfibrozil ) increases FAO , decrease VLDL formation and improve HDL.

Slide 62:

Synthesis Of Fatty Acid

Slide 63:

1. Acetyl CoA formation in the Cytoplasm from Citrate by ATP-lyase

Slide 64:

As with other carboxylation reactions, the enzyme prosthetic group is biotin . ATP-dependent carboxylation of the biotin, carried out at one active site1 , is followed by transfer of the carboxyl group to acetyl-CoA at a second active site 2. Acetyl-CoA Carboxylase catalyzes the 2-step reaction by which acetyl-CoA is carboxylated to form malonyl-CoA . 2. ACAC

Slide 65:

The primary structure of the mammalian Fatty Acid Synthase protein is summarized above. Fatty Acid Synthase in mammals is a homo- dimer & have an X-shape , with domains arranged as summarized at right.

Slide 66:

KS ACP FAS S S Cys Pan Acetyl/ Acyl Malonyl Acyl Carrier Protein (ACP) contains 4’’phosphopantheine, the SH of which is important for malonyl CoA carriage. Cysteine –SH (present in KAS ) is involved in acetyl or acyl CoA carriage. Since the two sites are important, FA synthase is active only in dimer form . Cys

Slide 67:

The condensation reaction (step 3) involves decarboxylation of the malonyl moiety, followed by attack of the resultant carbanion on the carbonyl carbon of the acetyl (or acyl) moiety.

Slide 68:

The b -ketone is reduced to an alcohol by H transfer from NADPH. Dehydration yields a trans double bond. Reduction by NADPH yields a saturated chain.

Slide 69:

Following transfer of the growing fatty acid from ACP -phosphopantetheine to the FAS - cysteine sulfhydryl, the cycle begins again , with another malonyl-CoA.

Slide 70:

Product release: When the fatty acid is 16 carbon atoms long, a Thioesterase (Deacylase) domain catalyzes hydrolysis of the thioester linking the fatty acid to Acyl Carrier Protein via 4’PP. The 16-C saturated fatty acid palmitate is the final product of the Fatty Acid Synthase complex.

Slide 71:

Regulation Of Fatty Acid Synthesis

Slide 73:

AMP-Activated Kinase catalyzes phosphorylation of Acetyl-CoA Carboxylase, causing inhibition . Insulin activates phospho-protein phosphatase , which in turn dephosphorylates ACAC switching it actively .

Slide 74:

[Citrate] is high when there is adequate acetyl-CoA entering Krebs Cycle. Excess acetyl-CoA is then converted via malonyl-CoA to fatty acids for storage. Citrate allosterically activates Acetyl-CoA Carboxylase.

Slide 75:

Fatty acid synthesis from acetyl-CoA & malonyl-CoA occurs by a series of reactions that are: in bacteria catalyzed by 6 different enzymes plus a separate acyl carrier protein (ACP) in mammals catalyzed by individual domains of a very large polypeptide that includes an ACP domain. Evolution of the mammalian Fatty Acid Synthase apparently has involved gene fusion . NADPH serves as electron donor in the two reactions involving substrate reduction. The NADPH is produced mainly by the Pentose Phosphate Pathway.

b-Oxidation & Fatty Acid Synthesis Compared:

b -Oxidation & Fatty Acid Synthesis Compared

Slide 77:

Fatty Acid Synthase is transcriptionally regulated . In liver: Insulin stimulates Fatty Acid Synthase expression. Thus excess glucose is stored as fat. Transcription factors that mediate the stimulatory effect of insulin include USFs (upstream stimulatory factors) and SREBP-1 . SREBPs (sterol response element binding proteins) were first identified for their regulation of cholesterol synthesis. PUFA diminish transcription of the Fatty Acid Synthase gene in liver cells, by suppressing production of SREBPs.

Slide 78:

Leptin : Leptin is a hormone produced by fat cells in response to excess fat storage. Leptin regulates body weight by decreasing food intake, increasing energy expenditure, and inhibiting fatty acid synthase & SREBP-1 expressions.

Slide 79:

Microsomal FA Elongation Beyond the 16-C length of the palmitate, the product of Fatty Acid Synthase elongates in microsomes and endoplasmic reticulum (ER). Fatty acid elongation is needed to provide tissue (Brain) with C24 FA which is needed for cerebroside synthesis (Myelination). Differences between types of FAS (Cyto FAS& Micro FAE) are: Cytosolic FAS Microsomal FAE FA synthase dimer Complex Enzymes are separate Acyl Carrier is ACP No ACP De Novo FA Elongation of FA

Slide 80:

ER Desaturases introduce double bonds at specific positions in a fatty acid chain. Mammalian cells are unable to produce double bonds beyond C 9, e.g., D 12 . Thus some polyunsaturated fatty acids are dietary essentials , e.g., linoleic acid, 18:2 cis D 9,12 (18 C atoms long, with cis double bonds at carbons 9-10 & 12-13). Synthesis of USFA

Slide 81:

Formation of a double bond in a fatty acid involves the following ER membrane proteins in mammalian cells: NADH-cyt b 5 Reductase , a flavoprotein with FAD as prosthetic group. Cytochrome b 5 , which may be a separate protein or a domain at one end of the desaturase. Desaturase , with an active site that contains two iron atoms complexed by histidine residues. Desaturation occurs in 2 steps: First hydroxylation (NADPH + H + & O2) followed by removal of H2O (Dehydratase) . Acyl CoA  OH-Acyl CoA  Enoyl CoA NADH,H & O2 - H2O

Synthesis of PUFA:

Synthesis of PUFA A coupled process of desaturation and elongation. Linoleic ( ω 6, 18: 2 ) γ - Linolenic ( ω 6, 18: 3 ) Dihomo γ - Linolenic ( ω 6, 20 : 3 ) Arachidonic ( ω 6, 20 : 4 ) Δ ase Δ ase

Slide 83:

Triglyceride Synthesis (Lipogenesis)

Slide 86:

Triglyceride Breakdown (Lipolysis)

Slide 87:

Regulation Of Lipolysis

Slide 88:

5` AMP 3`, 5` cAMP ATP Insulin Nicotinic A PGE GH T4 Catecholamines Adenylate Cyclase Phosphodiesterase + + Caffiene - Lipase b Inactive Active Lipase a Protein Kinase Phosphatase Regulation of Lipolysis N.B. Lipase= CAP Enz. Glycogen Syn. = AAD Enz.

Slide 89:

Eicosanoid Synthesis

Slide 90:

Arachidonic FA is released from phospholipids by hydrolysis catalyzed by Phospholipase A 2 . This enzyme hydrolyzes the ester linkage between a fatty acid and the OH at C2 of the glycerol backbone, releasing the fatty acid & a lysophospholipid as products. The fatty acid arachidonate is often esterified to OH on C2 of glycerophospho-lipids, especially phosphatidyl inositol. Phospholipase D Phospholipase A1

Slide 92:

Physiological Actions of Eicosonoids

Slide 93:

Physiological Actions of Eicosonoids

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Physiological Actions of Eicosonoids

Slide 96:

Non-steroidal anti-inflammatory drugs - Aspirin inhibit cyclooxygenase a ctivity of PGH 2 Synthase by acetylation . - Derivatives of ibuprofen compete with arachidonate. Corticosteroids are anti-inflammatory because they prevent inducible PG synthase and PL A 2 expression, reducing arachidonate release. (NSAIDs) : Singulair , a prophylactic anti-asthmatic drug inhibiting leukotrienes that causing broncho -constriction.

Slide 97:

Heme Fe - desaturase Peroxynitrite Nitric Oxide O 2 .- NOS Arachidonate Corticosteroids NSAIDs Singulair NOS inhibitors LOX PGH 2 PG/ PC/TX LT

Slide 98:

Inhibition of Platelet Aggregation

Slide 99:

More potent Platelet disaggregation effect by PGI3 > TXA3

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Phospholipid Synthesis

Slide 102:

1. Phosphoglycerides

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Phosphoglycerides (Cont.) CO2 (CH 3 ) 3 desaturase Plasmalogen ( Δ PE) PLA2 PAF (PLT Activating F) Surfactant Di- palmitoyl P Choline

Slide 104:

Phosphoglycerides (Cont.)

Slide 105:

2. Sphingolipids

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Slide 107:

Lipoproteins These are circulating particles containing the hydrophobic lipid. Differ in the ratio of protein to lipids, & in the particular apoproteins & lipids that they contain. They are classified based on their density: Chylomicron (largest; lowest in density due to high lipid/protein ratio; highest % weight triacylglycerols ) VLDL (very low density lipoprotein; 2nd highest in triacylglycerols as % of weight) IDL (intermediate density lipoprotein) LDL (low density lipoprotein, highest in cholesteryl esters as % of weight) HDL (high density lipoprotein; highest in density due to high protein/lipid ratio)

Slide 108:

Formation of lipoproteins: Intestinal epithelial cells synthesize triacylglycerols, cholesteryl esters, phospholipids, free cholesterol, and apoproteins, and load them on Apo B48 & Apo C II to assemble chylomicrons . Chylomicrons are secreted by intestinal epithelial cells, and transported via the lymphatic system to the blood. Apoprotein CII on the chylomicron surface activates Lipoprotein Lipase .

Slide 109:

As triacylglycerols are removed by hydrolysis, chylomicrons shrink in size, becoming chylomicron remnants with lipid cores having a relatively high concentration of cholesteryl esters. Chylomicron remnants are taken up by liver cells, via receptor-mediated endocytosis . The process involves recognition of apoprotein E of the chylomicron remnant by receptors on the liver cell surface. Liver cells produce , and secrete into the blood, very low density lipoprotein ( VLDL ). The VLDL core has a relatively high triacylglycerol content. VLDL has several apoproteins , including apoB-100 .

Slide 110:

MTP (microsomal triglyceride transfer protein), in the lumen of the endoplasmic reticulum in liver , has an essential role in VLDL assembly. MTP facilitates transfer of lipids to apoprotein B-100 while B-100 is being trans-located into the ER lumen during translation. Control of VLDL production : VLDL assembly is dependent on availability of lipids . Transcription of genes for enzymes that catalyze lipid synthesis is controlled by SREBP . Availability of Apo B-100 for VLDL assembly depends at least in part on regulated transfer of B-100 out of the ER for degradation via the proteasome.

Slide 111:

As VLDL particles are transported in the bloodstream, Lipoprotein Lipase catalyzes triacylglycerol removal by hydrolysis. With removal of triacylglycerols and some proteins, the % weight that is cholesteryl esters increases. VLDL are converted to IDL, and eventually to LDL. VLDL  IDL  LDL The lipid core of LDL is predominantly cholesteryl esters . Whereas VLDL contains 5 apoprotein types (B-100, C-I, C-II, C-III, & E), only one protein, apoprotein B-100 , is associated with the surface monolayer of LDL .

Slide 112:

Nascent-HDL apoA-I Liver VLDL apoB-100 apoCs apoE IDL LDL apoB-100 apoE apoB-100 apoB-48 CM apoCs Intestine Nascent-HDL apoA-I Site of Synthesis of Lipoproteins CM LDL HDL VLDL Apo B CE A C E

Slide 113:

CM VLDL IDL LDL HDL Lipoprotein Nomenclature and Composition Intestine Liver VLDL Liver Intestine Origin 40 20 10 1 % Pr A B C All Apo- 60 80 90 99 % Fat 5 55 90 TG 30 25 4 Chol α β pre - β NMF EP CM pre - β β α Anode

Slide 114:

Major Apolipoproteins and Their Function Apo Lipo Origin Function ApoA-I HDL Liver, intestine Activate LCAT, Cholesterol efflux via ABCA1 ApoB-100 VLDL, Liver Ligand LDL receptor, TG LDL transport from cells Apo(a) Lp(a) Liver Inhibits fibrinolysis ApoCII HDL, VLDL Liver Activates lipoprotein lipase ApoE VLDL, IDL Liver, intestine Ligand, LDL receptor, LRP receptor LCAT: lecithin: cholesterol acyltransferase ABCA1: ATP binding cassette protein A1 LRP: LDL receptor related protein

Key Enzymes in Lipoprotein Metabolism:

Key Enzymes in Lipoprotein Metabolism • Lipoprotein lipase (LPL): hydrolysis of triglyceride rich particles • Lecithin:cholesterol acyltransferase (LCAT): participates in removal of excess cholesterol from peripheral cells N.B. Lipoprotein (a): Liver derived LDL-like. It has higher protein content Apo (a) is complexed with Apo-B100 & Kringles (Plasminogen Analogs)  Prevention of clot lysis.

Reverse Cholesterol Transport Delivery of peripheral tissue cholesterol to the liver for catabolism Requires HDL, apoA-I and LCAT:

Reverse Cholesterol Transport Delivery of peripheral tissue cholesterol to the liver for catabolism Requires HDL, apoA-I and LCAT Peripheral Cell Chol HDL HDL CE HDL Chol ABCA1 Liver VLDL or LDL apoB LDLr SR-B1 Chol PL CE TG diffusion LCAT LCAT CE CE apoA-I Chol = unesterified cholesterol CE = esterified cholesterol PL = phospholipid LDLr = LDL receptor Nascent HDL Bile to gut Macrophage/ Foam cell Chol Bile acids

Slide 117:

☺ The cholesterol in LDL is then used by cells, e.g., for synthesis of cellular membranes. ☺ The LDL receptor was identified by M. Brown & J. Goldstein, who were awarded the Nobel prize. ☺ The LDL receptor is a single-pass trans-membrane glycoprotein with a modular design. ☺ Cells take up LDL by receptor-mediated endocytosis .

Slide 118:

The LDL-binding domain on the exterior side of the plasma membrane recognizes & binds apoprotein B-100 . Once the receptor with bound LDL is taken into a cell by endocytosis, the LDL-binding domain faces the lumen of the vesicle. The vesicle then fuses with an endosomal compartment. The cytosolic domain of the LDL receptor binds adapter proteins that mediate formation of a clathrin coat . This allows the receptor to be selected into budding vesicles.

Slide 119:

Regulation: Synthesis of LDL Receptor is suppressed by high intracellular cholesterol . This process involves decreased release of SREBP . Members of the SREBP family of transcription factors activate transcription of genes for the LDL receptor , as well as for enzymes essential to cholesterol synthesis such as HMG- CoA Reductase. The decreased synthesis of LDL receptor prevents excessive cholesterol uptake by cells. It has the deleterious consequence that excess dietary cholesterol remains in the blood as LDL.

Slide 120:

The lowered intracellular cholesterol that results from treatment with statin drugs, leads to activation of SREBP, increasing transcription of the gene for LDL receptor . Thus statins lower plasma cholesterol both by inhibiting HMG- CoA Reductase (decreasing cholesterol synthesis) and by promoting removal of LDL from the blood.

Slide 121:

HDL (high density lipoprotein) is secreted as a small protein-rich particle by liver (and intestine). One HDL apoprotein, A-1 , activates LCAT (Lecithin-Cholesterol Acyl Transferase), which catalyzes synthesis of cholesteryl esters using fatty acids cleaved from the membrane lipid lecithin. The cholesterol is scavenged from cell surfaces & from other lipoproteins.

Slide 122:

LCAT Nascent HDL LCAT: Disk to sphere transformation Mature HDL Cholesteryl ester + Lysolecithin apoA-I CE Cholesteryl ester (CE) Cholesterol Phospholipid ApoA-I L ecithin: C holesterol A cyl T ransferase ( LCAT ) Free cholesterol Cholesteryl ester Cholesterol + Lecithin

Slide 123:

Reverse Cholesterol Transport (RCT) The process whereby excess cholesterol in peripheral cells, especially foam cells, is returned to the liver for degradation and excretion. RCT involves apoA-I and LCAT as well as receptors on the liver for uptake of the excess cholesterol.

HDL Metabolism and Reverse Cholesterol Transport:

HDL Metabolism and Reverse Cholesterol Transport A-I Liver CE CE CE FC FC LCAT FC Bile SR- B I A-I ABC1 = ATP-binding cassette protein 1; A-I = apolipoprotein A-I; CE = cholesteryl ester; FC = free cholesterol; LCAT = lecithin:cholesterol acyltransferase; SR- B I = scavenger receptor class BI ABC1 Macrophage Mature HDL Nascent HDL

Slide 125:

Microsomal Transfer Pr Apo -B100 Assembly of VLDL, IDL & LDL Pre - VLDL Nascent VLDL Glycation CHO CE PL Circulating VLDL HDL Apo- C & E Apo - C TG IDL LP- Lipase LDL CETP Chol Chol LCAT

Slide 126:

VLDL HDL CETP CETP Apo A Apo B 100 LCAT MTP Liver TG Tissue Cholesterol Modification of Circulating Lipoproteins

Role of CETP in HDL Metabolism:

Role of CETP in HDL Metabolism A-I Liver CE CE FC FC LCAT FC Bile SR- B I A-I ABC1 Macrophage CE B CETP = cholesteryl ester transfer protein; LDL = low-density lipoprotein; LDLR = low-density lipoprotein receptor; VLDL = very-low-density lipoprotein LDLR VLDL/LDL CETP Mature HDL Nascent HDL CE SRA Oxidation

Role of Hepatic Lipase and Lipoprotein Lipase in HDL Metabolism:

Role of Hepatic Lipase and Lipoprotein Lipase in HDL Metabolism CM = chylomicron; CMR = chylomicron remnant; HDL = high-density lipoprotein; HL = hepatic lipase; IDL = intermediate-density lipoprotein; LPL = lipoprotein lipase; PL = phospholipase; TG = triglyceride B Kidney Endothelium B TG CMR/IDL C-II CM/VLDL HL LPL A-I CE TG HDL 2 PL A-I CE HDL 3 PL Phospholipids and apolipoproteins



Errors of Lipoprotein Metabolism:

Errors of Lipoprotein Metabolism Primary Hyperlipoproteinemia Type I: Apo-C II  LPL activity  TG Type II: Hyper β LP Apo-B100 Receptors LDL endocytosis ( (similar Wolman’s def. lysosmalCEase Type III: Dys β LP Apo-E  Broad Beta Band (LDL & IDL) Type IV: Hyper pre β LP Insulin Resistance  VLDL Type V: LCAT  RCT Discoid HDL Secondry Hyperlipoproteinemia : 20 % of Hyperlipaemia Diabetes Mellitus Hypothyroidism Nephrotic Syndrome Alcoholism Contraceptives Pancreatitis Obstructive Jaundice



Primary (Genetic) Causes of Low HDL-C:

Primary (Genetic) Causes of Low HDL-C ApoA-I  Complete apoA-I deficiency  ApoA-I mutations (e.g., ApoA-I Milano ) LCAT  Complete LCAT deficiency  Partial LCAT deficiency (fish-eye disease) ABC1  Tangier disease • Homozygous • Heterozygous  Familial hypoalphalipoproteinemia (some families) Unknown genetic etiology  Familial hypoalphalipoproteinemia (most families)  Familial combined hyperlipidemia with low HDL-C  Metabolic syndrome

Complete Apo A-I Deficiency:

Complete Apo A-I Deficiency Markedly reduced HDL-C levels and absent apoA-I Cutaneous xanthomas (some patients) Premature atherosclerotic vascular disease (some patients)

LCAT Deficiency and Fish-eye Disease:

LCAT Deficiency and Fish-eye Disease Both due to mutations in LCAT gene:  LCAT deficiency – complete Fish-eye disease – partial Common to both types of LCAT deficiency:  Markedly reduced HDL-C and apoA-I levels  Rapid catabolism of apoA-I and apoA-II  Corneal arcus  Premature atherosclerotic vascular disease (rare)

Tangier Disease:

Tangier Disease Autosomal codominant disorder due to mutations in both alleles of ABC1 gene Extremely marked reduction in HDL-C and apoA-I Markedly accelerated catabolism of apoA-I and apoA-II Cholesterol accumulation:  Enlarged orange tonsils  Hepatosplenomegaly  Peripheral neuropathy

Familial Hypoalphalipoproteinemia:

Familial Hypoalpha lipoproteinemia Due to mutations in one allele of ABC1 gene in some families, and of unknown genetic etiology in other families Moderate reduction in HDL-C and apoA-I Increased risk of premature atherosclerotic vascular disease

Secondary Causes of Low HDL-C:

Secondary Causes of Low HDL-C Smoking Obesity (visceral fat) Hypertriglyceridemia Drugs  Beta-blockers  Androgenic steroids  Androgenic progestins

CETP Deficiency:

CETP Deficiency Autosomal co-dominant; due to mutations in both alleles of CETP gene Markedly elevated levels of HDL-C and apoA-I Delayed catabolism of HDL cholesteryl ester and apoA-I & HDL particles enlarged and enriched in cholesteryl ester

Hepatic Lipase Deficiency:

Hepatic Lipase Deficiency Autosomal recessive, due to mutations in both alleles of hepatic lipase gene Modestly elevated levels of HDL-C and apoA-I Variable elevations in total cholesterol, triglycerides, and lipoprotein remnant particles No evidence of protection against atherosclerosis; possible increased risk of premature atherosclerotic vascular disease

Familial Hyperalphalipoproteinemia:

Familial Hyper alpha lipoproteinemia Autosomal dominant; molecular etiology unknown Modest to marked elevations in HDL-C and apoA-I Selective increased synthesis of apoA-I in some families Associated with longevity and protection against atherosclerotic vascular disease in epidemiologic studies

Secondary Causes of Increased HDL-C:

Secondary Causes of Increased HDL-C Extensive regular aerobic exercise Regular substantial alcohol intake Estrogen replacement therapy Drugs  Phenytoin

Slide 142:

Thrombosis Endothelial Plaque PDGF Cytokines Proteases Endothelial Injury

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Slide 144:

Cell layers adjacent to the lumen of arterial blood vessel. Development of an atherosclerotic plaque : Various conditions can initiate formation of a lesion in the endothelium lining the arterial lumen. Inflammatory response , including cytokine production that may be activated by oxidized lipids present in LDL . Risk factors include elevated circulating LDL, high blood pressure, exposure to nicotine, etc.

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Lipoproteins (e.g., LDL) leak across the endothelium and accumulate in the subendothelial space. They accumulate in part through binding to proteoglycans. Macrophages accumulate at the lesion and enter the subendothelial space. They ingest lipoproteins and appear as “ foam cells ” due to cytoplasmic lipid droplets.

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Smooth muscle cells may also migrate into the subendothelial space & become foam cells. As foam cells eventually die , they may release harmful cellular contents that can contribute to rupturing of the plaque and development of blood clots .

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Drugs for Treatment of Hyperlipoproteinemia Reducing plasma cholesterol Statins: target the liver, inhibits cholesterol biosynthesis, increases LDL receptors ER Nucleus HMG-CoA Reductase Cholesterol Stimulates LDLr gene LDLr LDLr Liver Cell HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase LDLr, LDL receptor; ER, endoplasmic reticulum Drugs Lovastatin, simvastatin, atorvastatin (Lipitor)

Bile Acid Seqestrants:

Bile Acid Seqestrants Bind and remove bile in intestine • Increases cholesterol conversion to bile • Increases LDL clearance • Lowers plasma cholesterol Drugs Cholestyramine Colestipol

Triglyceride Reducers:

Triglyceride Reducers Reduces synthesis of VLDL in liver Increases catabolism of VLDL Lowers plasma TG Increases HDL Drugs Gemfibrozil Fenofibrate Fibric Acids

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Cholesterol Absorption Inhibitor Ezetimibe • Blocks uptake of dietary cholesterol in small intestine. • Inhibits ABC transporter receptors on surface of intestinal absorptive cells. • Lowers plasma cholesterol • Used together with statin (lipitor): extremely powerful in reducing plasma cholesterol

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Disorders of Lipid Metabolism & Lipoproteins

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Cystic fibrosis ( CF ) Autosomal Recessive Disease Mutation of CFTR gene ( CF Trans-membrane Conductance Regulator)  chloride currency + Cl - in sweet ( Sweet Test) In pancreas, hydration  viscosity of pancreatic enzymes  stasis  pancreatic enz. deficiency  steatorrhoea (Loss of lipids in stool). Clinical Condition

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Obstructive biliary canals  loss of emulsification of lipids + loss of activation of lipases Jaundice + Steatorrhoea + Vitamin Deficiencies. Clinical Implications In cystic fibrosis, chronic pancreatitis or obstructive pancreatic duct  Steatorrhoea. Ezetimibe , a drug further reduce cholesterol absorption by enterocytes. Orlistat , a drug used in ttt of obesity is an inhibitor of pancreatic lipase and colipase. Any cause of steatorrhoea  bulky, greasy and offensive stool. Digestion and absorption of all elements of chime will be affected due to coating effect of fat

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Accumulation of Polyenoic A Zellweger’s Neurodisorder

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Defective Carnitine Transporting System

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Defective ACAD Autosomal Recessive Most common FAO inborn errors ttt by CHO-rich diet Inherited Acute fatty liver in pregnancy Akee tree Jamaican Hypoglycin ttt by MCFA

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Fatty Liver From 4 to 40 % increase of lipid content of liver. Replacement by fibrosis if condition is prolonged. It is imbalance between lipid income into liver and lipid secreted from liver. ATP MTP PL Lipotropic Factors Proteins TG VLDL CHO Depot Toxins (CCl4, Chloroform or Arsenic …) Pr. Ө Alcohol  increase NADH/NAD  acetaldhyde  Acetyl CoA FA Ethionine traps ATP Vit . Def.

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Vitamins Deficiency: Folic & B12  methyl carriage  Choline syn. Pyridoxine  inositol syn. Lipositol Increased: Biotin  stimulate appetite + decreased inositol syn. PL (& PUFA) Lipotropic Factors TG VLDL CHO Depot Fatty Liver (Cont.) Methionine, Glycine & betaine

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RDS ( Respiratory Distress Syndrome) Lung collapse due to deficiency of special lecithin ( D iPalmityl P hos P hatidyl C holine, DPPC ), which contains C1 & C2 palmitic a. DPPC is called surfactant, essential for alveolar integrity as it reduces the surface tension and that helps gaseous exchange across the alveolar membrane Mutation of SP genes and ABC gene contribute the occurrence of RDS. Treatment: Corticosteroids DPPC local spray

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MDS ( Multiple Disseminated Sclerosis) Replacement of phospholipids in myelin sheath by glial tissue (Nerve Demyelination of white matter) Decreased sphingomyelin, glycolipids &EA Plasmalogen. CSF show Immunoglobulins, phospholipids & Chol.Ester. Treatment: Corticosteroids

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Sphingolipidosis Ceramide Glu Gal NAGLA NANA Glucosidase Globosidase HA- ase Gala-ase Gaucher’s Tay-Sachs Generalized Gangliosidosis

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Sphingolipidosis (Cont.) Choline P Sphingosine FA Ceramide Niman-Pick Farber’s Sphingomyelin

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Thrombosis Endothelial Plaque PDGF Cytokines Proteases Endothelial Injury

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Ketosis Increased ketone bodies in blood (Ketonaemia > 3 mg/dl) and in urine (Ketonuria > 15 mg /day). Ketogenic conditions ( Decreased Insulin/Anti-insulin Ratio): - Starvation - DM - Low CHO + High Fat Diet - Severe Ms Exercise - Pregnancy Ketonuria is associated with loss of Na, K & NH 4 +  decreased HCO - in blood  Acidosis. Anti-ketogenics: CHO, Glycerol, Insulin and Proteins.

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Liver & Lipid Metabolism Lipogenesis VLDL assembly Ketogenesis Desaturation of FA Gluconeogenesis from Glycerol Phospholipids re-modulation (Lipoproteins synthesis , release and uptake. Activation (A), esterification (A&D) for storage & utilization (K)of Fat soluble vitamins. Cholesterol synthesis (& Vit D) and excretion .

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Desirable Lipid Levels in Adults Goal (mg/dl) * Lipid Less than 200 mg/dL Total cholesterol Less than 100 mg/dL Low-density lipoprotein (LDL) cholesterol More than 40 mg/dL High-density lipoprotein (HDL) cholesterol Less than 160 mg/dL Triglycerides Less than 2.8 Risk Factor (LDL/HDL)

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Integration in Metabolism

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Surfactants are adjuvants that reduce surface tension within the external surface layers of water. There are four different types of surfactants : Anionic Surfactants are negatively charged, and enhance foaming and other spreading properties. For example, shampoo for hair contains sodium or ammonium laureth sulfate, which is the preferred anionic surfactant for hair. Using an anionic surfactant in the greenhouse can cause problems with sprayers that have an agitator, or any system where the foam could disrupt water flow or pump suction . Cationic Surfactants are positively charged, and are often very toxic to plants as they can disrupt membrane ion balance. Cationic surfactants are not widely used for pest control, but they are more commonly used in heavy-duty cleaning compounds. Don’t grab a bottle of engine wash surfactant used to clean the tractor. The results can be devastating to plant materials . Amphoteric Surfactants , depending upon the pH of the solution, will form either a positive or negative charge in water. Their use in horticulture crop protection is rare. These products are used very specifically to match the properties of specific pesticide formulations to carrier components or other materials, and are generally not available for use in the greenhouse as a stand-alone product . Nonionic Surfactants do not have a charge in solution and are the most commonly used surfactants for the horticulture industry. When used properly, do not harm plants, remain stable, and do a good job of breaking water surface tension. However, application rate is critical .

HDL Metabolism in CETP Deficiency:

CETP HDL Metabolism in CETP Deficiency A-I CE FC FC LCAT A-I Macrophage B Delayed catabolism ABC1 HDL VLDL/LDL Nascent HDL CE

HDL Metabolism in Hepatic Lipase Deficiency:

HDL Metabolism in Hepatic Lipase Deficiency A-I Liver A-I CE TG CE HL Delayed catabolism HDL 2 HDL 3