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Acidi grassi e regolazione dell’espressione genica: aspetti fisio-patologici Gianna Ferretti Università Politecnica delle ...
Ipotesi  lipidica  ( Seven Countries Study)  Ruolo del  colesterolo  e  grassi animali  come responsabili delle patologie ...
<ul><li>Apporto eccessivo  di grassi e di colesterolo </li></ul><ul><li>Apporto squilibrato  tra vari acidi grassi contenu...
100 50 0 % Energy Low-fat meat Chicken Eggs Fish Fruit Vegetables (carrots) Nuts Honey 100 50 0 % Energy Fruit Vegetables ...
-4x10 6 -10000 1800 1900 2000 Tempo(anni) Percentuale di energia derivata  da acidi grassi (%) Grassi totali Acidi grassi ...
VLDL LPL CM Remnant acidi grassi liberi Lipidi   Trigliceridi Chilomicroni (CM) Effetto dei lipidi della dieta Acidi grass...
ox-VLDL  ox-HDL  Intake di acidi grassi ossidati LPL  ox-CM  VLDL assembly LPL 1 2 3 4 4 Intestino Fegato assorbimento Ef...
<ul><li>Substrati energetici  </li></ul><ul><li>Composizione delle membrane biologiche e proprietà chimico-fisiche </li></...
Acidi grassi e regolazione dell’espressione genica  via  sensing molecular switches J Clin Invest. 2004;114:94-103 J Biol ...
<ul><li>Il metabolismo lipidico nei mammiferi e nell’uomo è regolato da fattori di trascrizione  che regolano  geni coinvo...
Peroxisome proliferator-activated receptors  una famiglia di recettori nucleari che regolano  geni coinvolti nella sintesi...
Geni coinvolti nell’ossidazione degli acidi grassi Beta- Ossidazione perossisomi Beta- Ossidazione mitocondri Sintesi  aci...
Vetrino microarray  ( GeneChips ) Estrazione di RNA dai campioni Marcatura cDNA labelling kit Eccitazione dei fluorocromi ...
   HDL synthesis Dieta iperlipidica     PPAR     ABCA1    Lipid peroxidation <ul><li>inflammatory cytokines (TNF-  ,...
Acidi grassi saturi e monoinsaturi a confronto in soggetti in sovrappeso SFA-rich diet  (n=20) Dieta ricca di acidi grassi...
<ul><li>La dieta ricca in acidi grassi saturi  si riflette in un  aumento  dell’espressione di geni pro-infiammatori nel t...
Fish-oil supplementation induces anti-inflammatory gene expression profiles in human blood mononuclear cells <ul><li>Dose ...
12256 geni espressi  nei leucociti polimorfonucleati Supplemento EPA/DHA 1040 geni modificati  Supplemento Alto contenuto ...
PUFA milk shake (65% PUFA) MUFA milk shake (80% MUFA) SFA milk shake 70% SFA T0 T= 6 0re dopo assunzione Effetto di un mil...
13,365 geni espressi  nei leucociti polimorfonucleati PUFA milk shake 437 geni modificati  SFA milk shake 297 geni modific...
Acidi grassi e regolazione dell’espressione genica  durante la gravidanza
<ul><li>Conclusioni </li></ul><ul><li>Gli acidi grassi si  comportano come molecole idrofobiche ad azione ormono-simile </...
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Acidi grassi e regolazione dell'espressione genica: aspetti fisiolopatologici

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Acidi grassi e regolazione dell'espressione genica: aspetti fisiolopatologici.
Effetto dei grassi saturi e insaturi sull'espressione di geni legati al metabolismo lipidico e infiammazione

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Acidi grassi e regolazione dell'espressione genica: aspetti fisiolopatologici

  1. 1. Acidi grassi e regolazione dell’espressione genica: aspetti fisio-patologici Gianna Ferretti Università Politecnica delle Marche Ancona, 15 Settembre 2011
  2. 2. Ipotesi lipidica ( Seven Countries Study) Ruolo del colesterolo e grassi animali come responsabili delle patologie cardiovascolari. Patologie cronico-degenerative: Meccanismi molecolari e Markers biochimici Ipotesi infiammatoria Citochine proinfiammatorie Interleuchine TNFalfa Ipotesi ossidativa Ruolo del danno ossidativo alle principali macromolecole Radicali liberi , Antiossidanti endogeni ed esogeni Perossidazione lipidica delle LDL e HDL
  3. 3. <ul><li>Apporto eccessivo di grassi e di colesterolo </li></ul><ul><li>Apporto squilibrato tra vari acidi grassi contenuti nei trigliceridi presenti negli alimenti </li></ul>Acidi grassi: Apporti alimentari ed effetti sul metabolismo lipidico <ul><li>Rapporto tra acidi grassi monoinsaturi e acidi grassi poliinsaturi </li></ul><ul><li>Rapporto tra acidi grassi omega 3/ omega 6 </li></ul>Apporto di acidi grassi insaturi (trans) Rapporto tra acidi grassi saturi e insaturi Apporto di acidi grassi ossidati
  4. 4. 100 50 0 % Energy Low-fat meat Chicken Eggs Fish Fruit Vegetables (carrots) Nuts Honey 100 50 0 % Energy Fruit Vegetables Beans Meat Chicken Fish Processed foods Grain Milk/-products Isolated Carbohydrates Isolated Fat/Oil Alcohol 1.200.000 Generations between feast en famine Paleolithic era 2-3 Generations in energy abundance Modern Times Geni “paleolitici” e nuovi stili alimentari
  5. 5. -4x10 6 -10000 1800 1900 2000 Tempo(anni) Percentuale di energia derivata da acidi grassi (%) Grassi totali Acidi grassi saturi Acidi grassi omega 6 Acidi grassi trans Acidi grassi omega 3
  6. 6. VLDL LPL CM Remnant acidi grassi liberi Lipidi Trigliceridi Chilomicroni (CM) Effetto dei lipidi della dieta Acidi grassi Intestino
  7. 7. ox-VLDL ox-HDL Intake di acidi grassi ossidati LPL  ox-CM VLDL assembly LPL 1 2 3 4 4 Intestino Fegato assorbimento Effetto dei lipidi ossidati della dieta Ferretti G Effect Of Dietary Lipids On Paraoxonase-1 Activity And Gene Expression R Nutrition, Metabolism and Cardiovascular Diseases (in press)
  8. 8. <ul><li>Substrati energetici </li></ul><ul><li>Composizione delle membrane biologiche e proprietà chimico-fisiche </li></ul><ul><li>Trasduzione del segnale </li></ul>Acidi grassi e loro ruoli fisiologici <ul><li>Acidi grassi omega 3 </li></ul><ul><li>precursori di mediatori anti-infiammatori </li></ul><ul><li>TXA3, PGE3, LTB5 </li></ul><ul><li>Acidi grassi omega 6 </li></ul><ul><li>precursori di mediatori infiammatori </li></ul><ul><li>PGG2, LTB4, TXA </li></ul><ul><li>Regolazione dell’espressione di geni coinvolti nella sintesi o catabolismo lipidico (fegato, tessuto adiposo) </li></ul><ul><li>( Upregulation o Downregulation) </li></ul>
  9. 9. Acidi grassi e regolazione dell’espressione genica via sensing molecular switches J Clin Invest. 2004;114:94-103 J Biol Chem. 2006;28:934-44 Endocrinology. 2006;147:1508-16 Physiol Genomics. 2007;30:192-204 Am J Clin Nutr. 2007;86(5):1515-23 PLOS ONE 2008;3(2):e1681 BMC Genomics 2008; 9:231 BMC Genomics 2008; 9:262 J Biol Chem. 2008;283:22620-7 Arterioscler Thromb Vasc Biol. 2009;29:969-74. Plos One 2009;4(8):e6796 HEPATOLOGY 2010;51:511-522 Am J Clin Nutr. 2009; 90:415-24 Am J Clin Nutr. 2009 ;90:1656-64 Mol Cell Biology 2009;29:6257-67 Am J Clin Nutr. 2010;91:208-17 Dieta Acidi grassi nucleo Target gene
  10. 10. <ul><li>Il metabolismo lipidico nei mammiferi e nell’uomo è regolato da fattori di trascrizione che regolano geni coinvolti nella sintesi, nel catabolismo dei lipidi </li></ul><ul><li>e infiammazione </li></ul><ul><li>peroxisome proliferator-activated receptors (PPAR α , ß, γ1, and γ2), </li></ul><ul><li>sterol regulatory element binding protein-1 (SREBP-1), </li></ul><ul><li>hepatic nuclear factors (HNF-4 α and γ), </li></ul><ul><li>retinoid X receptor (RXR α), </li></ul><ul><li>liver X receptor (LXR α) </li></ul><ul><li>……… . </li></ul>Metabolic Regulation of Gene Transcription in Mammals Nutrienti e regolazione dell’espressione genica: Meccanismi molecolari
  11. 11. Peroxisome proliferator-activated receptors una famiglia di recettori nucleari che regolano geni coinvolti nella sintesi o catabolismo dei lipidi . Acidi grassi Membrana cellulare Membrana nucleare PPAR alfa - Affinità degli acidi grassi acidi grassi poliinsaturi (PUFA) > acidi grassi monoinsaturi (MUFA) > acid grassi saturi (SFA) Acidi grassi a lunga catena > acidi grassi a media e corta catena Idroperossidi ed eicosanoidi Target: Geni coinvolti nel catabolismo lipidico e infiammazione
  12. 12. Geni coinvolti nell’ossidazione degli acidi grassi Beta- Ossidazione perossisomi Beta- Ossidazione mitocondri Sintesi acidi grassi Sintesi trigliceridi Geni lipogenici SREBP1 Acidi grassi poliinsaturi (PUFA) e regolazione dell’espressione genic a sterol regulatory element binding protein-1 PPRE responsive element
  13. 13. Vetrino microarray ( GeneChips ) Estrazione di RNA dai campioni Marcatura cDNA labelling kit Eccitazione dei fluorocromi e valutazione segnale fluorescente ANALISI DEI DATI Rosso ( upregulation) Verde (downregulation) Giallo nessuna differenza DNA-microarray Tecnologia che permette di ottenere con un’unica analisi i profili di espressione di migliaia di geni, contemporaneamente.
  14. 14.  HDL synthesis Dieta iperlipidica  PPAR   ABCA1  Lipid peroxidation <ul><li>inflammatory cytokines (TNF-  ,IL-6,IL-1) </li></ul><ul><li>ROS formation </li></ul>Risposta infiammatoria Leukocyte infiltration 1 2 3 4 6 7 Intestino Fegato Assorbimento Effetto dei lipidi della dieta Ferretti G Effect Of Dietary Lipids On Paraoxonase-1 Activity And Gene Expression R Nutrition, Metabolism and Cardiovascular Diseases (in press)
  15. 15. Acidi grassi saturi e monoinsaturi a confronto in soggetti in sovrappeso SFA-rich diet (n=20) Dieta ricca di acidi grassi saturi (19%SFA,11%MUFA) Dieta ricca in acidi grassi monoinsaturi ( 11%SFA, 20%MUFA) <ul><li>Biopsia tessuto adiposo </li></ul><ul><li>Prelievo di sangue </li></ul>T=0 T=2 settimane T=10 settimane <ul><li>Biopsia tessuto adiposo </li></ul><ul><li>Prelievo di sangue </li></ul>Van Dijk et al. AJCN 2009
  16. 16. <ul><li>La dieta ricca in acidi grassi saturi si riflette in un aumento dell’espressione di geni pro-infiammatori nel tessuto adiposo </li></ul><ul><li>Diminuita espressione e diminuzione del livello plasmatico della adiponectina , una citochina anti-infiammatoria </li></ul><ul><li>La dieta ricca in acidi grassi Monoinsaturi si riflette in una diminuzione dell’espressione di geni pro-infiammatori nel tessuto adiposo </li></ul>SFA diet MUFA diet Acidi grassi saturi e monoinsaturi a confronto
  17. 17. Fish-oil supplementation induces anti-inflammatory gene expression profiles in human blood mononuclear cells <ul><li>Dose bassa di supplemento EPA/DHA (0,4g) , corrispondente a 2 porzioni di pesce a settimana </li></ul>Trattamento per 26 settimane N=351 soggetti >65 anni di età <ul><li>Supplemento Alto contenuto in oleico </li></ul><ul><li>Dose elevata di supplemento EPA/DHA 1,8g) corrispondente a 10 porzioni di pesce a settimana </li></ul>Bouwens et al. Am J Clin Nutr. 2009
  18. 18. 12256 geni espressi nei leucociti polimorfonucleati Supplemento EPA/DHA 1040 geni modificati Supplemento Alto contenuto in oleico 298 geni modificati Down-regulated 188 geni Up- regulated 537 geni Upregulated 110 geni Down -regulated 503 geni Geni coinvolti nella infiammazione Geni pro-aterogenici Overlap 140 geni Fish-oil supplementation induces anti-inflammatory gene expression profiles in human blood mononuclear cells
  19. 19. PUFA milk shake (65% PUFA) MUFA milk shake (80% MUFA) SFA milk shake 70% SFA T0 T= 6 0re dopo assunzione Effetto di un milk shake con il 70% delle calorie fornite da grassi (21 soggetti)
  20. 20. 13,365 geni espressi nei leucociti polimorfonucleati PUFA milk shake 437 geni modificati SFA milk shake 297 geni modificati Down-regulated 101 geni Up- regulated 225 geni Upregulated 196 geni Down -regulated 212 geni Geni coinvolti nello stress ossidativo, metabolismo del glutatione, infiammazione Overlap 146 geni
  21. 21. Acidi grassi e regolazione dell’espressione genica durante la gravidanza
  22. 22. <ul><li>Conclusioni </li></ul><ul><li>Gli acidi grassi si comportano come molecole idrofobiche ad azione ormono-simile </li></ul><ul><li>Tutti gli acidi grassi esercitano un ruolo regolatore dell’espressione genica ed è stata stabilita una relazione tra struttura delle molecole e loro effetto modulatore </li></ul><ul><li>L’effetto regolatore si osserva in diverse condizioni fisiologiche . </li></ul><ul><li>Le modificazioni osservate (up-regulation o down-regulation) si instaurano precocemente, in assenza di modificazioni significative dei lipidi plasmatici e/o alterazioni del metabolismo glucidico. </li></ul>

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