Craiova Medical

Vol 10, Nr 1, 2008

Studiu clinic
Evaluarea rolului hiperinsulinemiei i adipokinelor n proliferarea celulelor stelate hepatice i n extensia fibrozei n hepatita cronic C

MARIA MOA(1), MIHAELA VLADU(1), SIMONA G. POPA(1), I.R. DINU(1), VIOLETA COMNESCU(2), I. DIACONESCU(3), MIHAELA BCU(1), CAMELIA PNU(1), E. MOA(4)

Departamentul de Diabet Nutriie, Boli Metabolice, UMF Craiova; (2) Departamentul de Anatomie Patologic, Spitalul Clinic Judeean de Urgen Craiova; (3) Departamentul de Boli Infecioase, UMF Craiova; (4) Departamentul de Nefrologie, UMF Craiova.

(1)

Evaluation of the role of hiperinsulinemia and adipokines in the hepatic stellate cells proliferation and fibrosis progression in chronic hepatitis C
REZUMAT Hepatita cronic C este o afeciune ce se
extinde exponenial, implicnd consecine clinice, terapeutice i socio-economice. O serie de citokine i hormoni secretai la nivel adipocitar (leptina, rezistina, adiponectina, TNF) constituie conexiunea ntre acumularea de esut adipos i progresia i extensia fibrozei hepatice n hepatita cronic C i are drept consecin creterea insulinorezistenei (IR). Exist evidene substaniale care recunosc celulele stelate hepatice (CSH) ca principalele celule productoare ale matricei n procesul de fibroz hepatic. Hiperleptinemia a fost frecvent observat la pacienii cu IR indus de obezitate i are rol n promovarea progresiei fibrozei. Leptina promoveaz att proliferarea CSH dar i nhibarea apoptozei i aceasta pare a fi mediat de fosfoinozitol 3-kinaz. Rezistina stimuleaz secreia de citokine proinflamatorii de ctre CSH i detemin activarea NF-kB, demonstrnd o legatur direct ntre aceasta i fibrogeneza hepatic. O serie de molecule, incluznd TNF-, TGF-, au rol fibrogenetic prin inhibarea apoptozei CSH, contribuind la creterea numrului acestor celule n situaia unei injurii hepatice. Adiponectina are rol n meninerea CSH n forma inactiv i n regresia fibrozei hepatice prin inducerea apoptozei CSH activate. Asocierea dintre fibroza din HCC i IR indus de obezitate poate fi atribuit i nivelelor crescute ale insulinemiei. Hiperinsulinemia poate crete fibroza prin stimularea produciei de factor de cretere al esutului conjunctiv de la nivelul CSH. ntelegnd fiziopatologia CSH, tratamentul fibrozei hepatice este pe cale de a deveni o realitate. Evidene semnificative existente la momentul actual susin ideea c fibroza hepatic poate fi o condiie reversibil. Indicatori de prognostic ai fibrozei hepatice, CSH, pot deveni posibile inte terapeutice n prevenirea dezvoltrii cirozei hepatice.

ABSTRACT Chronic hepatitis C is a disease that

expands exponentially and implies clinical, therapeutical and socio-economic consequences. Some cytokines and hormones secreted by the adipocyte (leptin, resistin, adiponectin, TNF) represent the link between the growth of the adipose tissue and the progression and the extension of the liver fibrosis in chronic hepatitis C and they lead to the increase of insulin resistance (IR). Some evidence suggests that hepatic stellate cells (HSC) are the main matrix producers in liver fibrosis. Hiperleptinemia was frequently detected in patients with obesity induced IR and it promotes the fibrosis progression. Leptin promotes both the HSC proliferation but also the inhibition of apoptosis and this appears to be mediated by phosphoinositol-3-kinase. Resistin stimulates the secretion of the proinflammatory cytokines by the HSC and it leads to the activation of NF-kB, showing a direct link to liver fibrosis. Some molecules, including TNF- and TGF-, have a fibrogenetic role through the inhibition of HSC apoptosis, contributing to the multiplication of these cells when a liver injury occurs. Adiponectin has a part in keeping HSC in their inactive form and in the regression of liver fibrosis by inducing apoptosis in activated HSC. The association between fibrosis in CHC and obesity induced IR may be due to the increased levels of insulin. Hiperinsulinemia may develop fibrosis through stimulation of conjunctive tissue growth factor in HSC. The treatment of liver fibrosis may become true by understanding the physiopathology of the HSC. Significant evidence, nowadays, indicates that liver fibrosis may be a reversible condition. HSC, prognosis indicators of the liver fibrosis, may become possible therapeutic targets in preventing the development of the liver fibrosis.

CUVINTE CHEIE celule stelate hepatice, fibroz

hepatic, adipokine, obezitate, hiperinsulinism, hepatit cronic C

KEY WORDS hepatic stellate cells, liver fibrosis,

adipokines, obesity, hiperinsulinemia, chronic hepatitis C

Introducere

Prof. Univ. Dr. Maria Moa , Disciplina de Diabet Nutriie, Boli Metabolice, UMF Craiova

Maria Moa i colab: Evaluarea rolului hiperinsulinemiei i adipokinelor n proliferarea celulelor stelate hepatice i n extensia

Hepatita cronic C (HCC) este o afeciune ce se extinde exponenial, implicnd consecine clinice, terapeutice i socio-economice. nc de la descoperire, virusul hepatitic C (VHC) a fost recunoscut ca fiind o cauz major a HCC, cirozei i, respectiv, carcinomului hepatocelular. Se estimeaz actual un numr de 170 milioane persoane n lume infectate cu VHC, iar anual apar 3-4 milioane de cazuri noi [1]. Aproximativ 1020% din persoanele cu HCC dezvolt ciroz n 1020 ani, iar la aceti pacieni cancerul hepatic este ntlnit anual n procent de peste 5% [2]. Studii recente au artat c aproximativ 20% din persoanele cu HCC prezint obezitate i c obezitatea la aceti pacieni este asociat cu progresia fibrozei hepatice [3-6]. Avnd n vedere prevalena crescut a obezitii la pacienii cu HCC i extensia fibrozei la aceti pacieni, se impune identificarea mecanismelor care stau la baza acestor corelaii ct i a potenialelor strategii terapeutice de ameliorare a histologiei hepatice la pacienii cu obezitate i HCC.

Impactul adipocitului asupra extensie fibrozei n HCC

esutul adipos, considerat n trecut doar un depozit pasiv pentru energia n exces, este astzi recunoscut ca un sistem activ hormonal producnd numeroase molecule cunoscute sub numele de adipocitokine care exercit efecte centrale i periferice, regleaz metabolismul glucozei i al lipidelor [7,8,13,14] i moduleaz rspunsul imun [15,16]. O serie de citokine i hormoni secretai la nivel adipocitar constituie conexiunea ntre acumularea de esut adipos, progresia i extensia fibrozei hepatice n HCC. Majoritatea acestora, incluznd leptina, TNF i rezistina sunt secretate n exces la persoanele cu obezitate, n timp ce expresia i nivelele plasmatice ale adiponectinei sunt sczute n obezitate [13-15]. Leptina poate modula producia adipocitar de TNF iar adiponectina contracareaz efectele proinflamatorii ale TNF. Adipokinele au multiple roluri n patogeneza fibrozei hepatice. S-a observat c inta comun tuturor adipokinelor este reprezentat de celulele stelate hepatice (CSH). Leptina, rezistina, TNF i adiponectina au fost propuse ca factori determinai ai progresiei i extensiei fibrozei la pacienii cu HCC i obezitate. Obezitatea i n special obezitatea visceral este asociat cu un dezechilibru n producia de adipokine ce are drept consecin creterea insulinorezistenei (IR) [16]. IR este un factor important al gazdei la pacienii cu HCC, fiind corelat cu progresia i extensia fibrozei hepatice [17-19]. n dezvoltarea IR la pacienii cu HCC
6

este implicat att gazda ct i virusul prin diferite mecanisme [20,21]. Factorii gazdei sunt reprezentai de suprapondere sau obezitate, sedentarism, vrst naintat, diet bogat n lipide saturate i acizi grai trans [20,21]. Numeroase studii clinice au indicat faptul c IR este prezent n infecia VHC i se asociaz cu leziuni moderate i severe de fibroz [22,23]. Alteori, pacienii cu HCC fr fibroz au un grad de IR crescut fa de subiecii sntoi [12]. Mai multe studii au artat c IR i diabetul zaharat n HCC conduc la steatoz i fibroz [24-29], i prin aceasta cresc riscul de dezvoltare hepatocarcinomului. Exist studii care ncearc s explice mecanismul prin care IR produce fibroz hepatic. Se consider c IR determin direct stimularea CSH, inducnd secreie de matrice extracelular. IR pare s determine exacerbarea expresiei factorului de cretere i a altor citokine implicate n fibroz att la nivel hepatic ct i la nivelul esutului conjunctiv. La apariia inflamaiei i fibrozei ar putea contribui i hiperinsulinemia secundar IR, prin efectul demonstrat profibrogen, anomaliile receptorului PPAR gamma i disfuncia mitocondrial. n ceea ce privete VHC, date experimentale sugereaz c anumite componente proteice ale virusului C, n special proteina core i HS5A poate induce IR direct i asta se ntmpl trziu n cursul infeciei [30]. TNF poate media acest proces i s-a artat c stimuleaz IR la pacienii cu VHC prezent [31]. Fibroza este consecina esenial a injuriei hepatice cronice i reprezint mecanismul comun pentru insuficiena hepatica i pentru cea mai mare parte a complicaiilor clinice ale stadiilor finale ale bolii hepatice. Fibroza hepatic definit n 1978 de Organizaia Mondial a Sntii ca exces de colagen, n prezent se tie c este parte a unui proces dinamic continuu de remodelare a matricei extracelulare cu acumulare excesiv de proteine extracelulare, proteoglicani, laminin, elastin, colagen I, III, IV [32]. Fibroza se caracterizeaz histologic i biochimic prin creterea coninutului matricei extracelulare (MEC) [32]. Constituenii majori ai matricei extracelulare sunt reprezentai n mare msur n noua matrice format n timpul procesului de fibroza. Ca i n MEC normal, colagenul (n special tip I i III) i elastina sunt proteinele cele mai abundente, dar glicoproteinele sunt de asemenea prezente. Procentul tipului I de colagen este semnificativ crescut in noua matrice din fibroza hepatica [33]. Procesul este parial elucidat, n fibrogeneza hepatic atribuindu-se un rol important celulelor hepatice stelate [34-39].

Craiova Medical

Vol 10, Nr 1, 2008 matricei, rezultnd remodelarea matricei i acumularea de CSH active [32,46]. Celule cunoscute a interaciona cu celulele stelate sunt hepatocitele, celulele Kupffer, plachetele, celulele epiteliale, celulele endoteliale sinusoidale i neutrofilele. Fiecare dintre aceste celule vor elibera un subset de mediatori care vor avea diferite efecte asupra CSH. Factorul de cretere derivat din plachete (PDGF) i factorul de cretere i transformare (TGF-) sunt dou din cele mai bine caracterizate citokine n celulele stelate activate. Un numr crescut de studii identific PDGF ca mediatorul principal pentru proliferare, iar TGF- ca cea mai important citokin care stimuleaz fibrogeneza n celulele stelate [32,33,47-49].

Celula stelat hepatic factorul cheie n patogenia fibrozei hepatice

Exist evidene substaniale care recunosc celulele hepatice stelate (CSH) ca principalale celule productoare ale matricei n procesul de fibroz hepatic [32,33,40]. Analize cantitative ale CSH prin imunohistochimie s-au artat a fi utile n aprecierea ratei progresiei fibrozei hepatice n anumite situaii clinice. CSH au fost descrise pentru prima dat de von Kupffer n 1876. n 1980 Fridman et all. le-au identificat ca principala surs de colagen n ficat [41]. Originea i natura CSH rmne nc incerta. Actual autorii sugereaz o posibil origine epitelial a celulelor stelate i o transformare n esut mezenchimal dup activare. n ficatul normal CSH reprezint aproximativ 1,4% din volumul hepatic, ntr-o proporie de 3,6 6 celule la 100 hepatocite. Sunt tipic localizate n spaiul presinusoidal Disse ntre celulele endoteliale ale sinusoidelor i hepatocite. n starea neactivat CSH servesc drept depozit pentru vitamina A i sunt eseniale n reglarea homeostaziei acidului retinoic [42]. Celulele stelate sunt principalele celule implicate n producerea excesiv a MEC observate n fibroza hepatic. Ca rezultat al injuriei, CSH dup activare sau transdifereniere din celule de depozit pentru vitamina A n celule miofibroblastlike au caracteristici fenotipice diferite, cum ar fi promovarea migrrii celulare, adeziunii, creterii proliferrii, producerii de substane chemotactice capabile s recruteze celulele inflamatorii i, cel mai important, creterea capacitii fibrogenetice [32,43-45]. Procesul de activare a fost clasic divizat n dou faze distincte: I - Faza de iniiere, n care CSH sufer modificrile iniiale n celule miofibroblastice-like i devin responsive pentru citokine proliferative i fibrogenice prin stimularea receptorilor membranari. Odat ce CSH au indus expresia exagerat a receptorilor pentru citokine, fibrogeneza, proliferarea celular i alte mecanisme ale fenotipului activat al CSH, va fi perpetuat printr-o continu eliberare a mediatorilor de ctre esutul lezat cronic. II Faza de perpetuare n care numeroase tipuri de celule prezente n ficatul normal cum ar fi hepatocitele, celulele Kupffer, celulele endoteliale sinusoidale, plachetele i CSH activate, sunt implicate n producerea de citokine i ali mediatori care joac un rol important n aceast parte a procesului de fibrogenez [33,45]. Odat activate, CSH vor modifica expresia genelor componentelor MEC, enzimelor litice ale

Rolul adipokinelor i hiperinsulinemiei n fibrogeneza hepatic

Numeroase studii au indicat o serie de mediatori ce promoveaz proliferarea CSH i fibrogeneza, incluznd proteina tip 1 chemotactic pentru monocite [50], endotelina I [51], angiotensina II i unele adipokine [38]. O serie de molecule, incluznd factorul de necroz tumoral (TNF-), TGF-, au rol fibrogenetic prin inhibarea apoptozei CSH, contribuind la creterea numrului acestor celule n situaia unei injurii hepatice [49]. Specii reactive de oxigen produse de celulele Kupffer i hepatocite afectate au de asemenea rol n activarea CSH ca i n recrutarea de celule inflamatorii. Cum CSH secret citokine inflamatorii se formez astfel un cerc vicios [52]. Leptina este una din adipokinele secretate de celulele adipoase. Creterea nivelului leptinei se asociaz cu obezitatea i fibroza hepatic [53]. Leptina posed proprieti proinflamatorii in vitro, prin stimularea produciei de citokine proinflamatorii de ctre Th1 (IL-1, IL-6, IL-12, TNF) i prin scderea produciei citokinelor antiinflamatorii (IL-10) [54,55]. Hiperleptinemia a fost frecvent observat la pacienii cu IR, iar CSH prezint receptori specifici pentru leptin, astfel leptina poate juca un rol n activarea CSH i n promovarea progresiei fibrozei [56-58]. Leptina pare s joace un rol n activarea multiplelor semnale n CSH contribuind la inflamaia intrahepatic i fibrogenez. Evidene recente sugereaz c leptina promoveaz activarea factorului nuclear kB i expresia factorului chemotactic pentru monocite 1 (MCP1 Monocite Chemo Attractant 1) i VEGF (Vascular Endotelial Growth Factor). In vitro expunerea celulelor stelate la leptin determin creterea expresiei MCP1 i VEGF [59].

Maria Moa i colab: Evaluarea rolului hiperinsulinemiei i adipokinelor n proliferarea celulelor stelate hepatice i n extensia

n condiiile unei injurii acute hepatice induse de cloroform, administrarea leptinei in vivo la oareci se asociaz cu creterea expresiei MCP1, inflamaie i necroza, efecte mult mai puin severe la oarecii cu deficien de leptin [59]. Mecanismul exact prin care leptina promoveaz fibroza hepatic este necunoscut. n esuturile periferice leptina exercit control homeostazic al greutii corporale prin activitate inhibitorie asupra metabolismului glucozei i secreiei de insulin [60]. Ob-Rb este forma funcional a receptorului membranar asociat leptinei. Leptina induce fosforilarea formei funcionale a receptorului leptinei via Jak 2 kinazei (Janus Kinase 2) avnd ca rezultat fosforilarea ErK i Akt, dou elemente de transducie a semnalului asociate cu creterea celular. mpiedicnd fosforilarea indus de leptin, prin expresia exagerat a SOCS-3 sau prin nhibarea farmacologic, se previne fosforilarea Erk i Akt. n consecin, SOCS-3 blocheaz proliferarea CSH i fosforilarea receptorului leptinei Ob-Rb. Astfel, leptina nu doar promoveaz fibroza hepatic prin activarea genelor matricei extracelulare, dar i perpetu procesul fibrogenic prin inducerea direct a proliferrii CSH i prin inhibarea apoptozei CSH [70]. Leptina promoveaz att proliferarea CSH dar i nhibarea apoptozei i aceasta pare a fi mediat de PI3-kinaza (fosfoinozitol 3-kinaza) [38]. Rezistena la apoptoz constituie un important mecanism prin care CSH n ficatul lezat continu s promoveze modificri fibrotice care evolueaz spre ciroz. Aadar, leptina se identific ntr-o important citokin profibrogenic. O alt citokin proinflamatorie este TNF al carei nivel plasmatic este crescut la pacienii cu obezitate i HCC [12,31,63]. Productia de TNF este crescuta in HCC si este de asemenea implicat n dezvoltarea IR. Nivelul TNF se coreleaz cu progresia fibrozei, avnd abilitatea de a activa CSH i a promova formarea depozitelor de colagen. De asemenea, TNF poate inhiba activitatea PPAR gamma [64]. n adiie cu interferarea semnalului insulinic, creterea nivelului TNF este asociat cu scderea rspunsului la terapia antiviral [31]. Rezistina este o nou adipokin modulatoare a inflamaiei intrahepatice n codiiile unei injurii cronice. Observaiile c rezistina stimuleaz secreia de citokine proinflamatorii de ctre CSH cum ar fi MCP1 i IL-6 i detemin activarea NFkB, demonstreaz o legatur direct ntre aceasta i procesele inflamatorii de la nivelul ficatului [61,62,65]. n ciuda a numeroase studii, nu a fost
8

identificat pn in prezent un receptor specific pentru aceasta adipokin i se cunoate nc foarte puin despre mecanismul intracelular implicat. Totui, s-a evideniat creterea concentraiei intracelulare de calciu dup expunerea la CSH recombinate cu rezistin. Modularea farmacologic cu calciu, indic activarea de ctre rezistin a unui mecanism care implic fosfolipaza C, inozitol trifosfatul. Rolul adiponectinei la pacienii cu HCC nu este pe deplin definit. Numeroase studii au artat c adiponectina se coreleaz negativ cu indicele masei corporale i steatoza [66]. Dou studii au sugerat c adiponectina este corelat negativ cu inflamaia i necroza la pacieni cu HCC [67]. Studii recente caracterizeaz adiponectina ca fiind protectoare mpotriva injuriei hepatice. Adiponectina, secretat excesiv de adipocite are rol n meninerea celulelor stelate n forma inactiv i n regresia fibrozei hepatice prin inducerea apoptozei CSH activate. Adiponectina posed efecte fiziologice importante incluznd efect antiaterogen [68], iar hipoadiponectinemia sa artat a fi asociat cu cardiopatia ischemic cronic [69]. De asemena poate avea efecte antitumorale acionnd ca un reglator negativ al angiogenezei i inducnd apoptoza mediat celulelor endoteliale [60]. CSH inactive sintetizeaz adiponectin. Adiponectina se preconizeaz un potenial tratament antifibrotic n boala cronic hepatic. Asocierea dintre fibroza din HCC i IR indus de obezitate poate fi atribuit nivelelor crescute ale insulinemiei. Hiperinsulinemia poate crete fibroza prin stimularea produciei de factor de cretere al esutului conjunctiv de la nivelul CSH [70,71]. Nivelele crescute ale insulinemiei se coreleaz i cu creterea expresiei CTGF (connective tissue growth factor) n CSH.

Fig. 1. Mecanismele implicate n patogenia fibrozei la pacienii cu HCC i obezitate.

Mecanismele implicate n patogenia fibrozei par a fi genotip dependente. La pacienii infectai cu genotip viral 3 fibroza este mai mult rezultatul efectului citopatic al virusului, n timp ce pentru genotipul 1 fibroza pare a fi expresia sindromului

Craiova Medical metabolic. La pacienii cu genotip viral 3 gradul fibrozei se coreleaz cu viremia, n timp ce la cei cu genotip viral 1 cu nivelul leptinei i IR [72].

Vol 10, Nr 1, 2008

5. Camma`c Di Bona D et al. Effect of peginterferon alfa-2a on liver histology in CHC: a meta-analysis of individual patient data. Hepatology. 2004;39:333342. 6. Ortiz V, Berenguer M, Rayon J, Carrasco D, Berenguer J. Contribution of obesity to hepatitis Crelated fibrosis progression. Am J Gastroenterol. 2002; 79:2408-2414. 7. Fantuyyi G: Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 2005, 115: 911-919. 8. Day CP: From fat to inflammation. Gastroenterology 2006, 130: 207-210 9. Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 2005, 115: 911-919. 10. Guerre-Millo M. Adipose tissue and adipokines for better or woese. Diabetes Metab 2004, 30: 13-19. 11. Tataranni PA, Ortega E. A burning question: does an adipokine-induced activation of the immune system mediate the effect of overnutrition on type 2 diabetes? Diabetes 2005, 54: 917-927 12. Hui JM, Hodge A, Farrell GC, Kench JG, Krieketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 2004, 40: 46-54. 13. Bastard J, Maachi M, Lagathu C, Kim M, Caron M, Vidal H, Feve B. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw. 2006; 17(1):4-12. 14. Shoelson S et al. Inflammation and insulin resistance. J Clin Invest. 2006; 116:1793-801. 15. Sethi J, Vidal-Puig AJ. Thematic Review Series on Adipocyte Biology: Adipose tissue function and plasticity orchestrate nutritional adaptation. J Lipid Res.-Thematic review series, 2007 16. Ziccardi P, Nappo F, Giugliano G, Esposito K, Marfella R, Cioffi M, et al. Reduction of inflammatory cytokine concentrations and improvement of endothelial function in obese women after weight loss over one year. Circulation 2002, 105: 804-809. 17. G. Svegliati-Baroni et al. A Model of Insulin Resistance and Nonalcoholic Steatohepatitis in Rats. Role of PPAR- and n-3PUF Treatment on Liver Injury. The American Journ of Pathol. 2006, Vol. 169, No. 3 18. Strader D et al. AASLD practice guideline: diagnosis, management, and treatment of hepatitis C. Hepatology. 2004; 39:1147-1171. 19. Hadziyannis S et al. Peginterferon-alpha2a and ribavirin combination therapy in CHC: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004; 2;140:346-56. 20. Haag M, Dippenaar NG. Dietary fats, fatty acids and insulin resistance: shot review of multifaced connection. Med Sci Monit 2005, 11: RA359-RA367. 21. Bray GA. How do we get fat? An epidemiologic and metabolic approach. Clin Dermatol 2004, 22: 281288 22. Yan FM, Chen AS, Hao F, Zhao XP, Gu CH, Zhao LB, Yang DL, Hao LJ. Hepatitis C virus may infect extrahepatic tissues in patients with hepatitis C. World J Gastroenterol. 2000 Dec;6(6):805-811

Concluzii
Obezitatea se constituie ca o condiie metabolic i nu ca un simplu surplus ponderal. Pacienii obezi cu VHC prezent sunt candidai prefereniali pentru steatoz, steatohepatita, fibroz i rspuns sczut la tratament antiviral. Evidene semnificative existente la momentul actual susin ideea c fibroza hepatic poate fi o condiie reversibil. Scderea ponderal la pacienii cu HCV se asociaz cu diminuarea steatozei i fibrozei i scderea numrului CSH activate. Agonitii PPAR gamma inhib inflamaia i progresia fibrozei prin blocarea transcripiei factorului nuclear kB si a TGF 1 [73]. Inducerea apoptozei celulare se identific ntr-o promitoare opiune terapeutic, demonstrndu-se faptul c apoptoza CSH diminu fibroza hepatic. Terapia genic utiliznd supresori ai factorului nuclear kB care protejeaz CSH activate mpotriva apoptozei, poate determina scderea numarului acestora i ncetinirea progresiei fibrozei [76]. ntelegnd fiziopatologia CSH, tratamentul fibrozei hepatice este pe cale de a deveni o realitate. Indicatori de prognostic ai fibrozei hepatice [74,75], CSH pot deveni posibile inte terapeutice n prevenirea dezvoltrii cirozei hepatice [43,47-49,77]. Acknowledgements n prezent se desfoar un grant PNII-IDEI Proiecte de cercetare exploratorie: Insulinorezistena asociat obezitii, expresia hepatic SOCS3 i genotipul viraldeterminani ai extensiei fibrozei si nonresponsivitii la terapia cu Peginterferon n hepatita cronic viral C, director de proiect Prof. Dr. Maria Mota, grant finanat de CNCSIS. Datele prliminarii obinute indic existena unei corelaii semnificative statistic ntre parametrii antropometrici, valorile adipokinelor i a IR (cuantificat cu HOMA-IR) cu extensia fibrozei i steatozei hepatice. Bibliografie
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Adresa pentru coresponden: Prof dr Maria Moa, Disciplina de Diabet Nutriie Boli Metabolice, Facultatea de Medicin, UMF Craiova, Str Petru Rare, Nr 4, Craiova. E-mail: mmota53@yahoo.com, fax: 0251 502 246

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