Naringenin affords protection against lipopolysaccharide/D-galactosamine-induced acute liver failure: Role of autophagy

Acute liver failure (ALF) is considered a fatal clinical disorder and novel therapeutic interventions are manda-tory. Naringenin is a flavonoid with anti-inflammatory, antioxidant and antiapoptotic effects that have displayed beneficial effects in different animal models of ALF. The current study aimed at investigating the hep-atoprotective effect and the possible underlying molecular mechanisms of naringenin in lipopolysaccharide (LPS)/D-galactosamine (D-Gal) mouse model of ALF. Interestingly, naringenin pretreatment substantially alle-viated LPS/D-Gal-induced liver injury, enhanced survival, improved liver function and ameliorated histopath-ological liver changes. Importantly, naringenin potently activated autophagy as evidenced by the increased Beclin-1 expression and LC3 II/LC3 I ratio. Furthermore, results demonstrated that naringenin alleviated oxidative stress by inducing nuclear factor-erythroid 2-related factor 2 (Nrf2) and increasing hepatic SOD activity and GSH level as well as ameliorated endoplasmic reticulum (ER) stress. Likewise, naringenin mitigated LPS/D-Gal-triggered inflammation by suppressing NF-kappa B and NLRP3 pathways. Accordingly, apoptotic cell death pro-voked by LPS/D-Gal challenge was markedly attenuated as depicted by the decrease in caspase-3 and p53 in naringenin-treated mice. To investigate the contribution of autophagy to naringenin-conferred hepatoprotection, autophagy was inhibited using 3-methyladenine (3 MA). Strikingly, 3 MA co-treatment abolished the hep-atoprotective effect of naringenin, a finding that strongly suggests that naringenin-afforded protection is, at least in part, attributed to autophagy. Taken together, the present study revealed that naringenin exerted a prominent hepatoprotective effect by promoting autophagy with consequent attenuation of inflammatory responses, oxidative stress, ER stress and apoptosis. Our results provide evidence that naringenin use holds a promise as a potential therapeutic agent for ALF management.

Automated summary

This study revealed that naringenin exerted a prominent hepatoprotective effect in an LPS/D-Gal mouse model of ALF. This effect was achieved by promoting autophagy and attenuating inflammatory responses, oxidative stress, ER stress, and apoptosis. The results suggest that naringenin holds promise as a potential therapeutic agent for managing ALF.