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Intro to lipids Acyl group = Fatty Acid Sphingolipids ONLY in eukaryotes Sphingomyelins MOST Common Galactocerebrosides Focus on this one too Plants do NOT make cholesterol Lipid Storage Disease Fabry’s, Farber’s, Tay-Sach’s **** Digestion of Lipids (Look at Stick Diagram) Stomach, duodenum Absorption By small intestine Pancreatic lipase hydrolyzes TAG to form 2-MAG & 2 Acyl chains Lipolysis is accelerated by bile Chylomicrons contain (requires B48 apoprotein) TAG Phospholipids Cholesterol Fat Soluble Vitamins Why do they use lacteal system? Fate of absorbed lipid (exogenous) Glycerol (can become G3P Glycolysis) Cell membrane Adipose Beta oxidation Produced by liver is endogenous Lipid Catabolism In adipocytes Insulin activates lipase phophatase deactivates Hormone Sensitive TAG Lipase A (active) Epinephrine (Glucagon) + cAMP + Protein Kinase A + HS TAG Lipase A – P HSTAGL-A: TAG DAG + NEFA 3 NEFA + Glycerol NEFA travel in body bound to albumin Oxidation of Fatty Acids Beta Occurs mitochondria and peroxisomes Alpha Occurs in peroxisome Omega Occurs in Smooth ER TAG is subjected to lipolysis by LPL Before oxidation (in cytoplasm) Activation Step Thioester formed btw COOH & NEFA Thiol group of CoASH Acyl-CoA Catalysed by thiokinase Mitochondrial Matrix: LCFA *** Carnitine LCFA need carnitine to cross mito membrane CPT1 inhibited by Malonyl-CoA & CHO-rich meal (why?) Short & Medium can diffuse, but Long Chains need Carnitive VLCFA use peroxisomes Beta Oxidation Draw on board and talk about OHOL Know enzymes Energy chart (use chart) Diseases Look at website Beta Oxidation of odd chain FA’s Regular Beta oxidation until last 3 End up with Propionyl CoA Succinyl CoA (glucogenic) Beta Oxidation of unsaturated FA’s Produces less energy Uses Enoyl-CoA isomerase to change from cis to trans Oleic, Linoleic, Linolenic use this pathway Peroxisomes Peroxisomal alpha oxidation Shortening of fatty acid 1 C at a time Two Functions: Oxidation of branched chain fatty acids Production of odd chain fatty acids found in brain tissue Refsum’s Disease (know it) Phytanic acid cannot be converted to Pristanic Acid build up of phytanate and phytol Last step goes to mitochondria for beta oxidation Isobutyryl-CoA, Acetyl CoA and Propionyl-CoA Succinyl CoA (glucogenic) Beta oxidation Difference: deals with VERY long chain fatty acids (>20 C) Disorders See Clinicals Omega Oxidation In Smooth ER Ketone Bodies Due to excessive Acetyl-CoA High fat High Beta Oxidation (So High Acetyl CoA) Low carbohydrate Gluconeogenesis (OAA gets taken away) Types of Ketone Bodies 1. Acetone 2. Acetoacetate 3. Beta-hydroxybutyrate Ketogenesis chart (don’t have to know) Liver can MAKE Ketone Bodies, but cannot USE them (no enzyme) Enzyme: Succinyl-CoA:Acetoacetate transferase Ketogenesis HMG CoA Synthase is RATE LIMITING STEP Utilization Heart and Brain can use Ketone Bodies during starvation Cardiac Cells prefer Ketone Bodies Brain can use them grudgingly Uncontrolled Diabetes = pathological Fasting/Starvation = physiological Print Insulin Cascade Chart and Explain Control and Hormones Fatty Acid Synthesis (aka Biosynthesis) CHO Fat Acetyl-CoA is precursor to FA synthesis Glycolysis Pyruvate PDH Acetyl-CoA TCA Fatty Acid Synthesis Acetyl-CoA ACCase Malonyl-CoA FAS Palmitate Modified to Long Chain Fatty Acid Malonyl CoA inhibits CPT-1 Malate Citrate Shuttle (show picture and go over) ACCase (Acetyl-CoA Carboxylase) In mitochondria (why?) Multifunction protein Requires Biotin Components: Biotin Carboxylase Transcarboxylase Biotin Carboxyl Carrier Protein Picks up CO2 from HCO3 and turns Acetyl-CoA to Malonyl CoA Rate Limiting Step Draw Control Picture (pg21 lipid packet) Activated by Citrate Inhibited by Palmitate Phosphorylation is Deactivation Insulin activates Phosphatase removes Phosphate so activates ACCase Glucagon/Epinephrine Protein Kinase A (aka?) phosphorylate ACCase (deactivate) FAS Types I: Multifunctional, in animals II: Multienzyme, in plants III: Elongase (we got it) Three domains Homodimer CRDR KAS Domain I: Condensation Domain II: Reduction and Dehydration (he’ll write oxidized i/o dehydration) Domain III: Releases Palmitic Acid Has thioesterase that releases thioester bond with ACP Carbon Origin Start with Acetyl CoA Synthase Add Malonyl-CoA (3C) and lose CO2 (-1 C) So, it will ALWAYS run 7 times 1st two carbons from Acetyl-CoA, last 14 carbons from Malonyl-CoA Fate of Palmitic Acid Elongation Reactions In ER: In Mitochondria: Microsomal, Principle Way to Elongation At Carboxy End Two Carbons from Malonyl-CoA ACCase occurs in cytosol Uses Acetyl-CoA (why?) 1. Malonyl-CoA will inhibit CPT-1 Because Acyl is out and cannot be brought in 2. Bunch of ACCase in mitochondria Desaturation of Fatty Acids Mammals lack enzymes to desaturate beyond 9th position Mammals cannot synthesize Linoleic Acid (C18:2) 9, 12 alpha-linolenic acid (C18:3) 9, 12, 15 Arachadonic (C20:4) 5, 8, 11, 14 Omega Fatty Acids (ω or n) Total # of carbons – Last double bond (highest #) = omega # Oxidation and Synthesis (Page 27) Read Chart Out Regulation of Fatty Acids ACCase is Rate Limiting Step, so regulated Short Term + citrate - Palmitoyl CoA Long Term Gene Expression Increase in Glucose and decrease in fat (long term) TAG Synthesis Kennedy Pathway Know Phosphatase Step (Control Step) Three Acyl Transferase Cholesterol Acetyl-CoA HMG HMG CoA Reductase Mevalonate Isoprene Squalene (30 C) Isoprenaline + Isoprenaline (5 + 5) 10 C + Isoprenaline (5) 15 C + 15 C 10 C 15 C 30 C (Squalene) Squalene gets cyclised by Cyclase Lanosterol - 3 C Cholesterol (how many carbons? 27) HMG CoA Reductase Controlled by: Hormonal Control Glucagon phosphorylates and inactivates HMG CoA Reductase Insulin dephosphorylate and activates HMG CoA Reductase High cholesterol levels inhibits biosynthetic pathway by: Increasing rate at which HMG CoA reductase is degraded (shortens ½ life) Decreases rate of enzyme synthesis Drugs Look at website Inactivated by Phosphorylation ACCase, PDH, Glycogen Synthase, Bifunctional Protein, HMG CoA Reductase