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Backgrounds: Oxidative and inflammatory stress in the liver contributes to liver injury, increased cardiovascular risk and insulin resistance. Our previous study shows that Roux-en-Y Gastric Bypass (RYGB) improves oxidative stress in liver through Nrf2, an important transcription factor for anti-oxidative stress. We also found that LKB/AMPK/Sirt1 expression was increased in liver after RYGB. Here, we postulate that Sirt1 and Nrf2 work synergistically to attenuate oxidative and inflammatory stress in the liver after RYGB on obese rats.
Methods: Expression of TNFα, IL-6, glutathione-S-transferase (GST), Sirt1, PGC1α, Nrf1, and Nrf2 within the liver was measured in rats from RYGB and sham weight-matched control cohorts. The nuclear to cytosolic ratios of Sirt1, Nrf2, and NF-κB were measured as well. A corresponding set of in vitro experiments were done in the Kuffper cell line RKC1. The cells were treated with glucose and /or fatty acids in different doses to mimic gluocotoxicity and lipotoxicity. The cells were then treated with siRNA to knock down Sirt1. Afterwards, the expression levels and ratios of the above mentioned factors were measured.
Results: RYGB up-regulated Sirt1, PGC1α, Nrf1, Nrf2 and GST in liver (p<0.001), decreased NF-κB, TNFα, IL-6 and NOX2/4 (p<0.001) compared to the sham weight match control. In RKC1 cells, Sirt1 depletion down-regulated PGC1α, Nrf1, Nrf2 and GST(p<0.001). In contrast NF-κB, TNFα, IL-6 NOX2/4 (p<0.001) were increased significantly.
Conclusions: We suggest that the Sirt1/PGC1α/ Nrf1/Nrf2 pathways in liver may help to attenuate oxidative and inflammatory stress after RYGB procedure. Correcting the dysregulation of these molecules will benefit patients with obesity-induced metabolic syndromes.