Liver NF-kappaB and AP-1 DNA binding in obese patients.
Oxidative stress and insulin resistance (IR) are major contributors in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and in the progression from steatosis to nonalcoholic steatohepatitis (NASH). Our aim was to assess nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1) activation and Toll-like receptor 4 (TLR4) expression as signaling mechanisms related to liver injury in obese NAFLD patients, and examined potential correlations among them, oxidative stress, and IR. Liver NF-kappaB and AP-1 (electromobility shift assay (EMSA)), TLR4 expression (western blot), ferric reducing ability of plasma (FRAP), and IR evolution (HOMA) were evaluated in 17 obese patients who underwent subtotal gastrectomy with gastro-jejunal anastomosis in Roux-en-Y and 10 nonobese subjects who underwent laparoscopic cholecystectomy (controls). Liver NF-kappaB and AP-1 DNA binding were markedly increased in NASH patients (n = 9; P < 0.05) compared to controls, without significant changes in NAFLD patients with steatosis (n = 8), whereas TLR4 expression was comparable between groups. Hepatic NF-kappaB activation was positively correlated with that of AP-1 (r = 0.79; P < 0.0001); both liver NF-kappaB and AP-1 DNA binding were inversely associated with FRAP (r = -0.43 and r = -0.40, respectively; P < 0.05) and directly correlated with HOMA (r = 0.66 and r = 0.62, respectively, P < 0.001). Data presented show enhanced liver activation of the proinflammatory transcription factors NF-kappaB and AP-1 in obese patients with NASH, parameters that are significantly associated to oxidative stress and IR.
Videla
Luis A
LA
Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile. lvidela@med.uchile.cl
Tapia
Gladys
G
Rodrigo
Ramón
R
Pettinelli
Paulina
P
Haim
Daniela
D
Santibañez
Catherine
C
Araya
A Verónica
AV
Smok
Gladys
G
Csendes
Attila
A
Gutierrez
Luis
L
Rojas
Jorge
J
Castillo
Jaime
J
Korn
Owen
O
Maluenda
Fernando
F
Díaz
Juan C
JC
Rencoret
Guillermo
G
Poniachik
Jaime
J
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D002763:Cholecystectomy; D005234:Fatty Liver / Q000209:etiology / Q000601:surgery; D005260:Female; D015390:Gastric Bypass; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D009767:Obesity, Morbid / Q000601:surgery; D018384:Oxidative Stress; D051197:Toll-Like Receptor 4 / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D001786:Blood Glucose; D007328:Insulin; D008055:Lipids; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1