Complex Lipid Metabolism

Phospholipids (PL) or Sphingosine Sphingolipids PL are composed of an alcohol (ethanolamine, serine, choline, inositol) attached by a phosphodiester bridge to: Diacylglycerol Glycerophospholipids or Sphingosine Sphingolipids Phospholipids are amphopathic in nature: Hydrophilic head: phosphate + alcohol (e.g. serine, choline) Hydrophobic tail: fatty acids

Where are Phospholipids ? Cell membrane PL PL are the predominant lipids of cell membrane Hydrophobic portion of PL: is associated with the the nonpolar portion of the membrane constituents (glycolipids, proteins & cholesterol) Hydrophilic head of PL (polar): Extends outward facing intracellular or extracellular aqueous environment Non-membrane-bound PL with certain functions in the body: e.g. Components of lung surfactant Essential components of bile (solubilization of cholesterol)

Structure of Phospholipids 1- Glycerolphospholipids: with glycerol backbone 2- Sphingolipids (sphingomyelin):with sphingosine backbone

Glycerophospholipids (phosphoglycerides) Types: 1-Phosphatidic acid (PA) diacylglycerol + phosphate group on the 3rd carbon (ONLY) Phospatidic acid (PA) is the precursor of others 2-Phosphatidic acid (PA) derivatives: are formed of phosphatidic acid & an alcohol (bound to P group) Serine + PA phosphatidylserine (PS) Ethanolamine + PA phosphatidylethanolamine (PE) Choline + PA phosphatidylcholine (PC) inositol + PA phosphatidylinositol (PI) glycerol + PA phosphatidylglycerol (PG)

Cardiolpin (diphosphaidylglycerol) synthesized from phosphatidyl glycerol Structure: 2 PA bound through their P by 1 glycerol (2 PA + 1 glycerol) important component of inner mitochondrial membrane antigenic it is recognized by antibodies against Trponema pallidum bactri (bacteria causing syphilis)

Plasmalogens (ether glycerolphospholipids) Fatty acid in carbon 1 is replaced by an unsaturated alkyl group attached by an ether linkage to glycerol molecule Examples: Phosphatidalethanolamine (abundant in nerve tissue) Phosphatidalcholine (abundant in heart muscles)

Platelet-activating factor (PAF) - Fatty acid at C1 is replaced by Saturated alkyl group linked by an ether link to C1 - Acetyl residue (instead of fatty acid) at C2 PAF binds to surface receptors to induce thrombotic & acute inflammation: Activation of inflammatory cells Mediates hypersenesitivity Induce acute inflammatory reactions Induces platelet aggragation Induce neutrophils & alveoli to generate superoxide radicals

Synthesis of Phosphatidic Acid

Phosphatidic acid is the precursor of triacylglycerol All cells except mature RBCs can synthesize phospholipids Triacylglycerol (triglycetides) synthesis occurs essentially only in: liver adipose tissue lactating mammary glands intestinal mucosal cells

Synthesis of Phosphatidic acid Derivatives

Phosphatidylethanolamine (PE) & Phosphatidylcholine (PC) PE & PC are the most abundant PLs in most eukaryotes Synthesis: choline & ethanolamine (from diet of from turnover of body PLs) Choline or etyhanolamine are phosphorylated by kinases conversion to CDP-choline or CDP-ethanolamine diacylglycerol + CDP-choline (or CDP-ethanolamine) PE or PC Synthesis of choline is insufficient. So, reutilization of choline is important Choline is essential dietary nutrient with adequate intake of 550 mg for male & 420 mg for females

Synthesis of PC from phosphatidylserine (PS) in the liver When free choline levels are low PS is decarboxylated to PE by PS decarboxylase (requiring PLP, active form of vitamin B6) PE is methylated (3 methyl droups) to PC by methyl donor S-adenosylmethionine Why PC is important in the liver: The liver exports significant amounts of PC in the bile PC is a component of lipoproteins in blood

Role of Phosphatidylcholine (PC) in lung surfactant Dipalmitoylphosphatidylcholine (DPPC) or Dipalmitoyllecithin In DPPC, C 1 & 2 of glycerol are occupied by palmitate DPPC is synthesized by granular pneumocytes DPPC is the major lipid component of lung surfactant Extracellular fluid layer lining the alveoli Surfactant reduces the pressure needed to reinflate alveoli So, it prevents alveolar collapse (atelectasis)

Respiratory Distress Syndrome (RDS) occurs in preterm infants associated with insufficient surfactant production is a significant cause of neonatal death Ratio of DPPC/sphingomyelin (L/S) in amniotic fluid used to estimate lung maturity of newborn a ratio of 2 or more is evident of maturity of lung as it reflects major shift from sphingomyelin to DPPC synthesis occurs in pnemcytes at about 32 weeks of gestation Lung maturation can be accelerated by giving glucocorticoids to mothers shortly before delivery RDS in treated or prevented in newborns by intratracheal instillation of surfactant (natural or synthetic)

RDS may occur in adults when surfactant-producing pnemocytes are damaged (e.g. by immunosuppressive medication or chemotheraputic drugs)

Phosphatidylinositol (PI) Synthesized from inositol & CDP-diacylglycerol PI contains stearic acid on carbon 1 arachidonic acid on carbon 2 So, it is the reservoir of arachidonic acid in membrane (provides the substrate for prostaglandin synthesis)

Role of PI in signal transduction PI bound to membranes is phosphorylated to Phosphatidylinositol 4,5 bisphosphate (PIP2) PIP2 is degraded by phospholipase C to: Inositol 1,4,5- triphosphate (IP1,4,5) & diacylglycerol Phospholipase C is activated by protein G (a subunit) as a result of binding of hormone to its receptor on the cell membrane

Sphingomyelin sphingosine-based phospholipid A long chain fatty acid is attached to sphingosine to form ceramide Ceramide is bound to phosphorylcholine producing sphingomyelin. (Ceramide is the precursor of sphingomyelin) Sphingomyelin synthesis begins by condensation of palmitoyl CoA & serine by decarboxylation (reaction requires active vitamin B6, PLP)

Sphingosine + Fatty Acid Ceramide (Long Chain) Phosphorylcholine P-Choline (from Phosphatidyl Choline) Sphingomyelin

Sphingomyelin is a major lipid in nerve tissue membranes 1-Sphingomyelin of the myelin sheath contains predominantly longer-chain fatty acids such as lgnoceric & nervonic acid Myelin sheath is a layered membranous structure that insulates & protects neuronal fibres of CNS 2-Sphingomyelin of the grey matter of the brain contains primarily stearic acid

Degradation of phosphoglycerides

Phospholipase activity is also available in: 1- toxins & venoms 2- several pathogenic bacteria produce phosphlipases that dissolve cell membranes & allow the spread of infection

Degradation of Sphingomyelin P-Choline sphingomyelinase (a lysosomal enzyme) Ceramide ceramidase sphingosine + FA

Niemann-Pick disease (type A & B) Autosomal recessive less than 1:100,000 Deficiency in sphingomyelinase Inability to degrade sphingomyelin Type A: severe infantile (rare) lipid is deposited in liver and spleen ---enlarged Progressive neurodegeneration: as a result of deposition of sphingomyelin in CNS Death in early childhood Type B: less severe no damage (or little) damage to neural tissue but, spleen, liver & lung & bone marrow are affected death in early adulthood

GLYCOLIPIDS Molecules that contain carbohydrates & lipids are derivatives of CERAMIDE (Sphingosine backbone + long chain Fatty Acid) Ceramide + carbohydrate (mono- or oligosaccharide) Glycolipids ---------------------------------------------------------------------------- N.B. ceramide + P-Choline sphingomyelin

Importance of Glycolipids Essential components of all membranes of the body but are found in greatest amounts in nerve tissue They are located on the outer leaflet of plasma membrane where they interact with the extracellular environment Glycolipids are antigenic: e.g identified as source of blood group antigens Carbohydrate portion is the antigenic determinant Glycolipids are cell surface receptors e.g. for: cholera, tetanus toxins certain bacteria & viruses

Structure of glycolipids Carbohydrate (monosaccharide or oligosaccharide) attached to lipid (ceramide) by an O-glycosidic bond (glycosphingolipids) Type of glycolipid depends on number & type of carbohydrate: 1- Neutral glycosphingolipids (with no charge.i.e. no NANA,no sulfate) A. ceramide monosaccharides (cerebrosides) i. Galactocerebrosides : ceramide+ galactose most common cerebroside in membranes ii. Glucocerebrosides : ceramide + glucose In brain & peripheral nervous tissue (high concentration in myelin sheath) B. ceramide oligosaccharides (globosides) attaching additional monosaccharides to glucocerebrosides

2- Acidic glycolipid (with NANA or Sulfate) Have negative charge at physiological pH provided by N-acetylneuraminic acid (NANA) or sulfate groups Gangliosides (with NANA) ceramide oligosaccharides + one or more NANA in ganglion cells of CNS Sulfatides (with sulfate groups) galactocerebroside (with galactose is sulfated) in nerve cells & kidney

Glycolipids Neutral Acidic Ceramide monosaccharides (cerbrosides) Ceramide oligosaccharides (globosides) Gangliosides Ceramide oligosaccharide + NANA Sulfatides galctocerebroside with sulfated galactose Glucocerebroside Galactocerebroside

Synthesis of Glycospingolipids Synthesis occurs in ER & Golgi By specifig Glycosyl transferases Sequential addition of glycosyl monomers to acceptor molecule (ceramide) Added sugar is activated (e.g. UDP-gucose)

Degradation of Glycolipids Glycolipids are internalized to lysosomes by endocytosis Lysosomal enzymes cleave specific bonds in glycolipids Degradation is a sequential process

Prostaglandins & Related compounds EICOSANOIDS (origin from polyunstaurated fatty acids with 20carbons) Prostaglandins (PG) Thromboxanes (TX) Leukotrienes (LT)

Eicosanoids (derived from 20 C polyunsat. FA) Potent compounds Their action mediated by plasma & nuclear receptors not stored in tisues Have extremely short half-life (rapidly metabolized) Differ from true hormones in that Elicit both physiologic & pathologic responses Produced in very small amounts In almost all tissues (not by a specialized glands) Act locally (not transported in blood to distant sites)

Synthesis of PG & TX Sources of arachidonic acid Diet or cell membrane PL linoleic acid (18 carbons, 2 double bonds) elongation & desaturation Arachidonic acid (20 carbons, 4 double bonds) Arachidonic acid is the immediate precursor of the of PG Sources of arachidonic acid 1- Dietary linoleic acid 2- Phospholipids of cell membrane : by phospholipase A2

Synthesis of PGH2 PGH2 is converted to a variety of PGs & TXs Arachidonic acid is subject to oxidative cyclization by prostaglandin endoperoxidase synthase to yield PGH2 Prostaglandin endoperoxidase synthase has 2 catalytic activities: 1- COX (cycoloxygenase) 2- peroxidase PGH2 is converted to a variety of PGs & TXs

COX-1 Peroxidase Linoleic acid In diet Arachidonic acid COX Peroxidase PGH2 PG & TX

Isozymes of PG endoperoxidase synthase COX-1 constitutively synthesis. in most tissues required to maintain healthy gastric tissue, renal homeostasis & platelet aggregation (Physiological Role) COX-2 inducible in a limited number of cells in response to inflammation (substances from inflam.cells) resulting in increased PG synthesis causing pain, heat, redness & swelling of inflammation & fever in infection (Pathological Role)

Inhibition of PG synthesis 1- Steroidal anti-inflammatory agent (as CORTISOL) 1- Cortisol Inhibits phospholipase A2 activity So, the precursor arachidonic acid is not available 2- Cortisol inhibits COX-2 but not COX-1

So, prevent synthesis of PGH2 (anti inflammatory) 2- All non-steroidal anti-inflammatory agents (as aspirin, indomethacin & phenylbutazone) inhibits COX-2 So, prevent synthesis of PGH2 (anti inflammatory) BUT they inhibit COX-1 also with subsequent: damage to stomach & kidneys impaired clotting of blood (aspirin's toxicity) 3- Inhibitors of COX-2 (as celecoxib) maintain the physiologic functions of COX-1 while having anti-inflammatory power (inh. of COX-2)

Role of PG in plateletet homeostasis Thromboxane A2 (TXA2) produced by activated platelets promotes adherence & aggregation of platelets So, promotes formation of blood clots (thrombotic) Prostacyclin (PGI2) produced by vascular endothelial cells inhibits platelet aggregation So, prevents formation blood clots (anti thrombotic)

Aspirin has antithrombogenic effect Basis of Low-dose aspirin therapy In platelets As aspirin inhibits TXA2 productionin platelets by irreversible inhibition of COX-1 as platelets can not synthesize more COX-1 (no nucleus) So, TXA2 synthesis is permanently inhibited in platelets In endothelium Although COX-1 is inhibited also in endothelium. However, this is not permanent as more COX-1 can be synthesized (endothelium is nucleated) So, prostacyclin synthesis is not inhibited in endothelium Basis of Low-dose aspirin therapy To avoid risk of stroke & heart attacks by decreasing formation of thrombi