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Fatty Acid Handling

Fatty Acid Handling. Beta-oxidation FA transport Integration of metabolic signaling. Fatty Acid/ b -oxidation Cycle. 1x FADH2 1x NADH Acetyl-CoA 3x NADH+ 1xFADH2. Acyl(n)-CoA + NAD + + FAD  Acyl(n-2)-CoA + Acetyl-CoA + NADH +FADH 2. Carnitine palmitoyltransferase.

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Fatty Acid Handling

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  1. Fatty Acid Handling • Beta-oxidation • FA transport • Integration of metabolic signaling

  2. Fatty Acid/b-oxidation Cycle • 1x FADH2 • 1x NADH • Acetyl-CoA • 3x NADH+ • 1xFADH2 • Acyl(n)-CoA + NAD+ + FADAcyl(n-2)-CoA + Acetyl-CoA + NADH +FADH2 Carnitine palmitoyltransferase Fatty acid elongation Acyl-CoA Acyl-CoA synthase FAD Acyl-CoA dehydrogenase Acyl-CoA FADH2 acetyl-CoA acyltransferase Acetyl-CoA Didehydroacyl-CoA Acyl-CoA hydrase CoA-SH 3-hydroxyacyl-CoA dehydrogenase Hydroxyacyl-CoA Oxoacyl-CoA NADH NAD+

  3. Fatty acid/carbohydrate oxidation • Oxygen • CnH2n + 3/2 n O2n CO2+ n H2O • CnH2nOn +n O2 n CO2 + n H2O • Respiratory Quotient CO2/O2 • 0.67 Fatty acids • 1.00 Carbohydrates • Adenine electron transporters • 6-C glucose6 NADH + 2 FADH2 (3:1) • 16-C FA  32 NADH + 16 FADH2 (2:1)

  4. Reactive oxygen • FADH2 oxidative stress • Succinate; saturated FA • FADH2 + Fe3+ FADH • + H+ + Fe2+ • Fe2+ + H2O2Fe3+ + OH- + OH• • FADH2 more completely reduces UQ than does NADH Acyl-CoA Acyl-CoA FADH2 FAD UQ O2 Acyl-CoA dehydrogenase Acyl-CoA oxidase ETF:QO oxidoreductase FADH2 FAD UQH2 H2O2 Didehydroacyl-CoA Didehydroacyl-CoA

  5. Lipogenesis • De novo synthesis of fatty acid • Mostly liver (human; diet) • Cytoplasmic – ACC expression • Malonyl-CoA • Carboxylation of Acetyl-CoA • Working substrate for FAS • Fatty acid synthase • Sequentially transfers 2x C of Malonyl-CoA to fatty acid chain • 16-C palmitoyl-CoA Acetyl-CoA Acetyl-CoA Carboxylase Malonyl-CoA Fatty Acid Synthase Fatty acid Fatty Acid Synthase

  6. Free fatty acids from triglycerides • FFA cleavage from circulating lipoproteins • Protein/cholesterol carriers: Lipoprotein • Density inversely correlates with lipid • Correlates with cholesterol/FA (except HDL) • VLDL & LDL to IDL • Lipoprotein lipase (LPL) • HDL scavenges cholesterol & facilitates IDL breakdown • Triglycerides are retained in intracellular droplets • Don’t fit in membrane (no phosphate) • Not water soluble

  7. Mitochondrial import of fatty acids • FAAcyl-CoA Acyl-Carnitine Acyl-CoA Cytoplasm Intermembrane Matrix Working substrate Boron & Boulpaep

  8. Mitochondrial Transport • Carrier protein (FABP) • Long chain acyl-CoA synthetase (LCAS) • Cross outer membrane via porin • Convert to acylcarnitine in intermembrane • Cross inner membrane via carnitine:acylcarnitine transferase • Convert back to acyl-CoA in matrix

  9. Regulation of lipid metabolism • Substrate/Allosteric • Palmitate inhibits insulin signaling • Malonyl-CoA inhibits FA transport to mt • Esp muscle, where ACC is mitochondrial • Citrate activates acetyl-CoA carboxylase • Palmitoyl-CoA inhibits ACC • Phosphorylation • AMP dependent kinase inhibits ACC • FAT/CD36 translocation

  10. Allosteric regulation of FA metabolism Carnitine Palmitoyltransferase Fatty Acid Synthetase ACC Malonyl-CoA Palmitoyl-CoA Citrate B-oxidation NADH Citric Acid Cycle Acetyl-CoA Citric acid cycle products promote FA synthesis FA synthesis intermediaries inhibit FA import

  11. Fatty acids Energy dense (37 kJ/g) Abundant (95%) O2 delivery limit Diffusion limit CHO Low density (17 kJ/g) Limited supply (5%) Hydrated (67 wt%) Lower O2 requirement Readily available Metabolic substrate selection Substrate selection is an issue for fed/fasted state and for overall activity Lipolysis rate (%VO2) Glcolysis rate (%VO2) McClelland, 2004 Total metabolic rate (%VO2 max)

  12. Signaling integration • Insulin/IGF-1 • GLUT4 translocation • InsRIRS-1PI3KPDKPKB --|GSK--|GS mTORp70S6k/4EBP1 • Fatty acids • Inhibit pyruvate dehydrogenase • Inhibit insulin signaling • FADAGPKC--|IRS-1 • Activate glycogen synthase

  13. AMP kinase • Allosterically activated by AMP • Adenylate kinase: 2 ADP  AMP + ATP • ADP levels insensitive to energy state PFKglycolysis --|GSGlyconeogenesis --|ACCMalonyl CoA--|CPTFA oxidation --|ACClipogenesis TSC2--|mTOR…protein synthesis --|HMGCoAcholesterol synthesis

  14. Hormonal Regulation • Insulin • Glucagon • Thyroid hormone (Triiodothyronine ) • Steroid • T3TR ?CaMKKβ AMPK Complex III/IV proteins, PGC-1 GLUT4 • Epinepherine (adrenaline) • Tissue specific: muscle/liver • AdbARGsACcAMPPKA • GPglycogenolysis • lipolysis

  15. Peroxisome Proliferator • PPAR-a/b/g(nuclear hormone, fatty acid sensor) • Transcriptional complex • PPAR(a/b/g), PGC-1(a/b), NRF-1/2, CREB • Subunits of Complex I-V; FAT; GLUT4 • Mitochondrial biogenesis • Transcriptional Pathways • InsulinAkt--|FOXO--|PGC-1 • Ca2+CaMKCREBPGC-1 • Glucagon/stressPKACREBPGC-1 • AMPK?PGC-1 • Post-Translational, too FADH2 O2 Peroxisome H2O2 FAD FADH2 UQ Mitochondria FAD UQH2

  16. PPAR/PGC signaling ↓ plasma NEFA Visceral FA subcutaneous ↑ insulin sensitivity ↑ mitochondria ↑ congestive heart failure ↑ fluid retention Fernandez-Marcos & Auwerx, 2011

  17. Close relation between nutritive status and growth • Insulin/IGF via PI3K • Glycolysis/lipolysis • Protein synthesis • Differentiation • AMP-Kinase • Glycolysis/lipolysis • Protein synthesis • IGF inhibition • AcetylCoA/CoA • Inhibit pyruvate dehydrogenase • NADH converts oxaloacetate to malate, reduces TCA intermediaries, including citrate • Growth hormone release • NAD+/NADH increases with cell confluence

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