Abstract

The p66(Shc) protein mediates oxidative stress-related injury in multiple tissues. Steatohepatitis is characterized by enhanced oxidative stress-mediated cell damage. The role of p66(Shc) in redox signaling was investigated in human liver cells and alcoholic steatohepatitis. HepG2 cells with overexpression of wild-type or mutant p66(Shc), with Ser(36) replacement by Ala, were obtained through infection with recombinant adenoviruses. Reactive oxygen species and oxidation-dependent DNA damage were assessed by measuring dihydroethidium oxidation and 8-hydroxy-2'-deoxyguanosine accumulation into DNA, respectively. mRNA and protein levels of signaling intermediates were evaluated in HepG2 cells and liver biopsies from control and alcoholic steatohepatitis subjects. Exposure to H2O2 increased reactive oxygen species and phosphorylation of p66(Shc) on Ser(36) in HepG2 cells. Overexpression of p66(Shc) promoted reactive oxygen species synthesis and oxidation-dependent DNA damage, which were further enhanced by H2O2. p66(Shc) activation also resulted in increased Erk-1/2, Akt and FoxO3a phosphorylation. Blocking of Erk-1/2 activation inhibited p66(Shc) phosphorylation on Ser(36). Increased p66Shc expression was associated with reduced mRNA levels of anti-oxidant molecules, such as NF-E2-related factor 2 and its target genes. In contrast, overexpression of the phosphorylation defective p66(Shc) Ala(36) mutant inhibited p66(Shc) signaling, enhanced anti-oxidant genes, and suppressed reactive oxygen species and oxidation-dependent DNA damage. Increased p66(Shc) protein levels and Akt phosphorylation were observed in liver biopsies from alcoholic steatohepatitis compared to control subjects.

Autore Pugliese

• Pacelli Consiglia

Tutti gli autori

• Perrini S. , Tortosa F. , Natalicchio A. , Pacelli C. , Cignarelli A. , Palmieri V.O. , Caccioppoli C. , De Stefano F. , Porro S. , Leonardini A. , Ficarella R. , De Fazio M. , Cocco T.M. , Puglisi F. , Laviola L. , Palasciano G. , Giorgino F.

Titolo volume/Rivista

AMERICAN JOURNAL OF PHYSIOLOGY: GASTROINTESTINAL AND LIVER PHYSIOLOGY

Anno di pubblicazione

2015

ISSN

0193-1857

ISBN

Non Disponibile

Numero di citazioni Wos

Nessuna citazione

Ultimo Aggiornamento Citazioni

Non Disponibile

Numero di citazioni Scopus

4

Ultimo Aggiornamento Citazioni

Non Disponibile

Settori ERC

Non Disponibile

Codici ASJC

Non Disponibile