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CASTIGLIONE, GIULIA (2009) Effetti metabolici in vitro degli inibitori delle deacetilasi istoniche su colture primarie di epatociti di ratto. [Tesi di dottorato]

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Abstract (inglese)

Histone acetylation/deacetylation are pivotal epigenetic mechanisms responsible for regulating chromatin structure and DNA transcription, respectively leading to a higher o a lesser degree of accessibility to transcription factors and RNA polymerase, i.e. turning on/off genetic expression. It has been described that histone deacetylase inhibitors (HDAIs) can influence hepatic DNA expression and tumor cell lines differentiation but few data about their effects on hepatocytes are available.
Freshly isolated Sprague-Dawley rat hepatocytes seeded on matrigel were cultured in control medium or in medium containing one of the following HDAIs: sodium butyrate (NaBu, 500 nM), valproic acid (VPA, 2 mM) or tricostatin A (TSA, 10 mM). After 4 days, cell viability and function were tested by albumin secretion (sandwich ELISA, normalizing the data with the protein content assayed by the Bradford’s method with Comassie Blue), albumin expression (RT-PCR analysis), urea synthesis after ammonia challenge (colorimetric method), cytotoxicity (LDH release measurement) and cell proliferation (BrDU incorporation).
Albumin secretion doubled after hepatocyte exposure to NaBu in comparison to controls (92.35 ±18.97 ?g/mg protein vs 44.36 ±7.81 ?g/mg protein; p=0.02) while it was inhibited by VPA (25.09 ± 3.02 vs 44.36 ±7.81 ?g/mg protein; p=0.03) and unaffected by TSA (46.9 ± 9.12 ?g/mg protein vs 44.36 ±7.81 ?g/mg protein; p=0.83). A similar behaviour was observed at RT-PCR analysis of albumin expression (data are relative values compared to controls which are by default 1; VPA: 2.2; NaBu: 12.6; TSA: 1.8). Urea metabolism was preserved in all conditions (controls: 25.47 ± 4.06 ?g/mg protein/h; VPA: 23.45± 4.87 ?g/mg protein/h, p=0.75; NaBu: 30.53 ± 6.98 ?g/mg protein/h, p=0.54; TSA: 25.89 ± 5.97 ?g/mg protein/h, p=0.95). Cells were significantly less viable when exposed to NaBu (54.26 %, p<0.001) or VPA (40.12 %, p=0.0097) than controls (70.74%) while TSA was less cytotoxic (67.85 %, p=0.56). Hepatocyte proliferation was increased with VPA (19.82 ± 3.19 BrDU-positive cells/mm2) and decreased with NaBu (2.05 ± 0.84 BrDU-positive cells/mm2) when compared to controls (5.88 ± 0.70 BrDU-positive cells/mm2).
NABU appears to be a differentiating agent on cultured hepatocyte, being able to stimulate albumin expression and production. Urea synthesis was however unaffected. NaBu appears to be less hepatotoxic than VPA, which provides a good proliferative stimulus. TSA played a quasi neutral role. These results suggest a possible use of HDAIs to improve hepatic specific functions in bioartificial liver devices.

Abstract (italiano)

L’acetilazione e la deacetilazione del DNA sono meccanismi epigenetici cruciali responsabili della regolazione della struttura della cromatina e della trascrizione del DNA, che consentono una maggiore o minore accessibilità ai fattori di trascrizione e alla RNA polimerasi, inducendo o inibendo rispettivamente l’espressione genica. In letteratura è descritto che gli inibitori della deacetilazione degli istoni (HDACIs = histone deacetylase inhibitors) possono influenzare il DNA inducendo la traduzione di geni tipicamente espressi nelle cellule del fegato ed il differenziamento di linee cellulari tumorali verso il pattern epatico, tuttavia sono ancora pochi i dati disponibili sui loro specifici effetti sugli epatociti.
Epatociti di ratto Sprague-Dawley appena isolati sono stati seminati su piastre con substrato di matrigel e coltivati con medium di controllo o con medium contenente uno dei seguenti HDACIs: il sodio butirrato (NaBu, 500 nM), l’acido valproico (VPA, 2 mM) e la tricostatina A (TSA, 10 mM). Dopo 4 giorni sono stati determinati i seguenti parametri: la funzionalità del metabolismo epatico tramite l’analisi della secrezione di albumina (sandwich ELISA, normalizzando i dati per il contenuto proteico misurato con il metodo di Bradford tramite il Blu di Comassie), l’analisi dell’espressione genica di albumina (analisi di Real Time PCR, RT-PCR), la quantificazione della sintesi di urea (realizzata mediante metodo colorimetrico con il carico di ammoniaca), la stima della citotossicità (quantificazione del rilascio di latticodeidrogenasi [LDH] mediante spettrofotometria) e della proliferazione cellulare (incorporazione di bromodesossiuridina [BrDU] mediante microscopia a fluorescenza).
La secrezione di albumina è risultata raddoppiata dopo l’esposizione degli epatociti al NaBu rispetto ai controlli (92.35 ± 18.97 ?g/mg proteine contro 44.36 ± 7.81 ?g/mg proteine; p = 0.02), mentre è stata inibita dal VPA (25.09 ± 3.02 ?g/mg proteine contro 44.36 ± 7.81 ?g/mg proteine; p = 0.03) e non è influenzata dal TSA (46.9 ± 9.12 ?g/mg proteine contro 44.36 ± 7.81 ?g/mg proteine; p = 0.83). L’analisi dell’espressione di albumina tramite RT-PCR conferma tali risultati (i dati sono espressi come valori relativi rispetto ai controlli i quali per convenzione hanno valore 1; VPA = 2.2; NaBu = 2.6; TSA = 1.8). Il metabolismo dell’urea è risultato inalterato (controlli = 25.47 ± 4.06 ?g/mg proteine/ora; VPA = 23.45 ± 4.87 ?g/mg proteine/ora, p = 0.75; NaBu = 30.53 ± 6.98 ?g/mg proteine/ora, p = 0.54; TSA = 25.89 ± 5.97 ?g/mg proteine/ora, p = 0.95).
Le cellule sono risultate significativamente meno vitali se esposte al NaBu (54.26 %, p <0.001) ed al VPA (40.12 %, p = 0.0097) rispetto ai controlli (70.74%), mentre il TSA si è dimostrato meno citotossico (67.85 %, p = 0.56). La proliferazione degli epatociti è risultata incrementata nell’esposizione al VPA (19.82 ± 3.19 cellule BrDU-positive/mm2, p <0.01) mentre è diminuita con il NaBu (2.05 ± 0.84 cellule BrDU-positive/mm2) rispetto ai controlli (5.88 ± 0.70 cellule BrDU-positive/mm2, p <0.01).
Il NaBu sembra quindi essere un agente di differenziazione per gli epatociti in grado di stimolare l’espressione genica dell’albumina e la sua secrezione. Tuttavia la sintesi di urea sembra non esserne influenzata. Il NaBu è risultato meno epatotossico del VPA, il quale costituisce peraltro un buono stimolo proliferativo. Il TSA gioca un ruolo quasi neutro ai dosaggi testati. Questi risultati suggeriscono di approfondire un possibile utilizzo degli HDACIs per incrementare le funzioni tipiche degli epatociti non solo in vitro ma anche nei dispositivi per il fegato bioartificiale.

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Tipo di EPrint:Tesi di dottorato
Relatore:REALDI, GIUSEPPE
Dottorato (corsi e scuole):Ciclo 21 > Scuole per il 21simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > FISIOPATOLOGIA CLINICA
Data di deposito della tesi:29 Gennaio 2009
Anno di Pubblicazione:29 Gennaio 2009
Parole chiave (italiano / inglese):epatociti inibitori delle deacetilasi istoniche (HDACIs = histone deacetylase inhibitors)
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/09 Medicina interna
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Scienze Mediche e Chirurgiche
Codice ID:1611
Depositato il:29 Gen 2009
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