phospholipid

STRUCTURE - Backbone is either glycerol (glycerophospholipids) or sphingosine (sphingomyelin). - Glycerophospholipids: glycerol + 2 fatty acids (positions C1 usually saturated, C2 usually unsaturated) + phosphate at C3 + a polar head group (choline, ethanolamine, serine, inositol, or glycerol). - Amphipathic: polar head faces water, nonpolar tails face inward, so phospholipids spontaneously form bilayers, micelles and liposomes.

MAJOR TYPES AND KEY FUNCTIONS - Phosphatidylcholine (lecithin): the most abundant membrane phospholipid. It is a bile and surfactant component. Dipalmitoylphosphatidylcholine (DPPC) is the main surfactant lipid made by type II pneumocytes. - Phosphatidylethanolamine (cephalin): membrane component, especially in the inner leaflet. - Phosphatidylserine: normally on the inner leaflet. Externalization on the outer leaflet is an "eat me" signal for apoptosis, and it is the surface for coagulation factor assembly on activated platelets. - Phosphatidylinositol: precursor of PIP2, which phospholipase C cleaves into IP3 (releases Ca2+ from the ER) and DAG (activates protein kinase C). It also anchors proteins via GPI anchors (deficiency causes paroxysmal nocturnal hemoglobinuria, PNH, because of defective decay-accelerating factor (DAF) and CD59 anchoring). - Sphingomyelin: found in myelin sheaths and cell membranes. It accumulates in Niemann-Pick disease (sphingomyelinase deficiency). - Cardiolipin (diphosphatidylglycerol): inner mitochondrial membrane. It is the antigen in the false-positive VDRL/RPR in syphilis. - Plasmalogens: ether-linked phospholipids. They are deficient in Zellweger syndrome (peroxisomal disorder).

SYNTHESIS AND DEGRADATION - Synthesized in the smooth ER, with CDP-diacylglycerol or CDP-choline/ethanolamine as activated intermediates. - Phospholipases: A2 releases arachidonic acid (the precursor of prostaglandins and leukotrienes, and the step inhibited by corticosteroids via lipocortin). Phospholipase C generates IP3 and DAG. Pancreatic phospholipase A2 digests dietary phospholipids. - Lysosomal storage diseases arise from defective degradation of the sphingolipid class (Niemann-Pick, Tay-Sachs and others).

CLINICAL CORRELATIONS 1. Neonatal respiratory distress syndrome: surfactant deficiency from prematurity (type II pneumocytes mature around 35 weeks) causes increased alveolar surface tension, atelectasis and hyaline membranes. The amniotic fluid lecithin:sphingomyelin (L/S) ratio is <1.5-2 in immature lungs. Risk factors are maternal diabetes (insulin delays maturation) and C-section. Antenatal corticosteroids speed lung maturation. Treatments include exogenous surfactant and CPAP. Complications: patent ductus arteriosus, intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity and bronchopulmonary dysplasia. 2. Antiphospholipid syndrome: autoantibodies (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I) cause arterial and venous thrombosis and recurrent pregnancy loss. Labs show a prolonged aPTT that does not correct on mixing study, and a false-positive RPR/VDRL. Treat with heparin and warfarin, and with low-dose aspirin and heparin in pregnancy. 3. Cell membrane fluidity: increased by unsaturated or shorter fatty acids and decreased by saturated or longer chains and by cholesterol at physiologic temperatures. Cholesterol acts as a fluidity buffer. 4. Membrane asymmetry: flippases keep phosphatidylserine and phosphatidylethanolamine on the inner leaflet. 5. Drug-induced phospholipidosis: cationic amphiphilic drugs (amiodarone, chloroquine) cause lysosomal phospholipid accumulation (lamellar bodies). 6. Lipid digestion: phospholipids (lecithin) in bile help emulsify fats and keep cholesterol soluble in mixed micelles. Low phospholipid or bile acid relative to cholesterol promotes cholesterol gallstones. Phospholipids also form the outer shell of lipoproteins (chylomicrons, VLDL, LDL, HDL).

HIGH-YIELD MNEMONIC - "Lecithin = Lung" (DPPC surfactant). Sphingomyelin stays constant as gestation progresses, so the L/S ratio rises as lecithin rises.