Liver NF‐κB and AP‐1 DNA Binding in Obese Patients

Abstract

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‐κB (NF‐κB) 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‐κB 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‐κB 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‐κB activation was positively correlated with that of AP‐1 (r = 0.79; P < 0.0001); both liver NF‐κB 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‐κB and AP‐1 in obese patients with NASH, parameters that are significantly associated to oxidative stress and IR.

Silibinin modulates lipid homeostasis and inhibits nuclear factor kappa B activation in experimental nonalcoholic steatohepatitis

“…41 NFkB activity is directly related to parameters of oxidative stress in the liver of obese patients. 42 Of note, the use of polyphenolic antioxidants, such as curcumin, determines NFkB inhibition displaying beneficial effects in experimental NASH. 10 The inhibition of NFkB exerts therapeutic effects in different mouse models of NASH.…”

Increased expression of c-Jun in nonalcoholic fatty liver disease

“…Saturated FFAs activate this proinflammatory transcription factor in hepatocytes, 45 and enhanced AP-1 activation has been demonstrated in obese patients with NASH. 46 AP-1 is a homo-or heterodimer consisting of proteins belonging to the c-Jun, c-Fos, ATF and JDP families, 47 with c-Jun being the best-characterized AP-1 component. The nuclear import of c-Jun is mediated by multiple mechanisms 48,49 and nuclear c-Jun levels correlate with AP-1 target gene activity.…”

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis

“…The increased availability of FFA in the liver promotes FFA oxidation and increases the production of free radicals leading to lipoperoxidation, DNA and protein damage, endogenous antioxidants depletion, and mitochondrial damage [13]. Oxidativenitrosative stress further triggers the activation of inflammatory pathways [14,15]. Similarly to the liver, cardiac lipotoxicity is associated with increasing reactive oxygen species (ROS) and reactive nitrogen species (RNS) production, which leads to DNA damage and death of myocardiocytes [16,17].…”