Note from last lecture:!- HDL also takes Ch back to liver via scavenger receptor SR-BI!- alanine --> liver --> covert to glutamate ---(glutamate dehydrogenase)--> NH4+ + alpha ketoglutarate!- in muscle: !!!Learning Objectives 1) Recognize the basic phospholipid and sphingolipid structures that form the lipid bilayers of all cell membranes. 2) Appreciate the differences in lipid composition of different membranes w/in a cell. 3) Know what an eicosanoid lipid is and their biological functions. 4) Understand the importance of cyclooxygenase in eicosanoid synthesis and the role of cyclooxygenase inhibitors in medicine. 1) Recognize the basic phospholipid and sphingolipid structures that form the lipid bilayers of all cell membranes. - Phospholipids!- Amphipathic molecules that form the basic structural unit of all cell membranes!- Most common = glyceropholipids= syn. on glycerol backbone w/fa at pos. 1 and 2, 3 pos.= phosphate + hydrophilic head groups!- common phospholipids are all off of: phosphatidyl (glycerol + 2 fa's + phosphate)!- hydrophilic head, hydrophobic tail-- can have kinks --> inhibit packing!- they form the basic lipid bilayer of all membranes!- phospholipid diffusion is rapid in leaflet <--->!- phospholipid diffusion is slow to flip leaflets - Phospholipids play a # of Critical Biological Roles!- Phosphatidylserine (PS): found on cytoplasmic face of pm, recognition signal for clearance of RBCs or cells going thru apoptosis!- Phosphatidylinositol: minor membrane lipid, precursor to several signaling proteins (ex. critical to insulin signaling)!- Phosphatidylcholine-dipathmitoyllecithin: major lipid comp. of surfactant in lung --> prevents collapse of alveoli !- neonatal respiratory distress syndrome (RDS) in preme's related to reduced levels of dipalmitoyllecithin, 15-20% of neonatal deaths in developed countries from this!- surfactant reduces the the surface tension in lung alveoli, syn. of it is increased by glucocorticoids which are given to women in preterm labor to decrease risk of RDS!- Biosynthesis of Phosphatidylcholine (Lecithin)!- Sphingolipids!- major group of complex membrane lipids based on backbone of sphingosine= a long chain amino alcohol- has part from serine + part from palmitate!- all spingolipids are derived from ceramide - ceramide= intermediate in syn. and degradation of sphingomyelin and glycospingolipids!- syn. is enzymatically driven (not template driven ex. DNA->RNA) - Blood Group Antigens - Blood group antigens (A, B, O) are surface GLYCOLIPIDS exposed on external surface on RBC!- People don't make antibodies to their own antigens, but can to those from other peeps!- Type O: someone w/o GalNAc or Gal transferases and present H on their RBC!- Type AB: have both transferases and display both A and B substances - Degradation of sphingolipids occurs in the lysosome via stepwise removal of sugars and other constituents - Defects in the degradative enzyme lead to accum of intermediates in damaging amts!- Prenatal diagnosis can be performed on fibroblasts from amniocentesis!- Many lysosomal storage diseases affect degradation of sphingolipids (ex. Tay-Sachs) 2) Appreciate the differences in lipid composition of different membranes w/in a cell. - Lipid composition varies between different cellular membranes !- asymmetric distribution of phospholipids and glycolipids in pm of RBCs 3) Know what an eicosanoid lipid is and their biological functions. - Eicosanoids: Lipid Signaling Molecules!- signalling molecules made from oxidation of 20 C fatty acids (like arachnidonic acid) that act locally (paracrine) by binding to cell surface receptors!- Major classes incl: prostaglandins, thromboxanes, prostacyclins, leukotrienes!- Potent modulators the inflammatory response, some are PRO-inflammatory and some are ANTI-inflammatory!- Regulate smooth m. contraction, bp, bronchoconstriction, bronchodilation, platelet aggregation,and other things!- Syn. from polyunsatr. fatty acids that are 20 C's derived from dietary essential fatty acids (linoleic and linolenic acid)!- precursors incl. omega3 and omega6 fatty acids, products made from diff. precursors have diff. physio effects!- humans: most common used precursos for biosyn.= arachidonic acid 4) Understand the importance of cyclooxygenase in eicosanoid synthesis and the role of cyclooxygenase inhibitors in medicine. - Biosynthesis of Eicosanoids!- First and most reg. step= release of precursor fatty aicds from 2-pos. of a membrane glycerophospholipid by phospholipase A2 - Activity of phospholipase A2 stim. by some histamine, cytokines to reg. eicosanoid synthesis!- Phospholipase A2 in venom of insects and snakes!- Cyclic/Cyclooxygenase Pathway!- Initial step in formation of prostaglandins, thomboxanes, and prostacyclins = formation of a 5C ring by cyclooxygenase!- Two isoforms of cyclooxygenase: constitutive (COX1) and inducible (COX2)!- COX1: expressed in almost all tissues, help produce eiconsanoids for normal physio functions, resp. for stomach bleeding and stimulating platelet aggregation (in you inhibit it --> inhibit platelet aggregation)!- COX2: induced by cytokines and growth factors in response to inflammation!- expressed highly in inflammed tissues!- Both are INHIBITED by non-steroid anti-inflammatory drugs ex. aspirin, ibuprofen!- Cyclooxygenase (COX) Inhibitors!- Pharma devel. specific COX inhibitors and thought they'd act as anti-inflamms w/o side effects of general COX inhibitors (GI bleeding, antiplatelet activity), but they were assoc. increased risk of heart attacks and stroke!- Cylooxygenase Pathway!- PGG2 (formed by COX) can be metabolized to # of lipid second messengers, each molecule acts locally and has a short biological half-life !!!!!!!!- Linear/Lipoxygenase Pathway!- forms lipid epoxides and hydroxylated derivs of arachidonic acid --> form leukotrienes!- Leukotrienes= powerful vasoconstrictors, mediate many inflamma actions!- Half life is longer than prostaglandins, hours!- Singular= LTC4 antagonist --> reduces lung inflammation and treats asthma !- 1 Baby Aspirin a day --> Reduces Heart Disease - Aspirin acetylates COX1 and COX2 --> inactivates them !- --> blocks production of thromboxane A2 (which normally increases platelet agg and forms a clot, stops bleeding)!- Platelet agg also forms unwanted clots that block blood flow and cause heart attacks and stroke, so inhibiting this w/aspirin decreases the chance of these events!- Why are Omega 3 Fatty Acids Healthy? -
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