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

• Published in: Archives of biochemistry and biophysics Vol. 717; p. 109121
• Main Authors: Ahmedy, Omaima A., Salem, Heba H., Sayed, Noha H., Ibrahim, Sherehan M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.03.2022
• Subjects: Acute liver failure; Animals; Anti-Inflammatory Agents - pharmacology; antioxidants; Antioxidants - pharmacology; apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Beclin-1 - genetics; Beclin-1 - metabolism; biophysics; Caspase 3 - metabolism; caspase-3; Disease Models, Animal; endoplasmic reticulum; ER stress; Flavanones - pharmacology; Galactosamine - metabolism; hepatoprotective effect; histopathology; Humans; Inflammation; lipopolysaccharides; Lipopolysaccharides - metabolism; Liver; liver failure; Liver Failure, Acute - chemically induced; Liver Failure, Acute - prevention & control; liver function; Male; Mice; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Naringenin; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Signal Transduction; Superoxide Dismutase-1 - metabolism; therapeutics; Tumor Suppressor Protein p53 - metabolism; ER stress; Acute liver failure; Oxidative stress; Inflammation; Naringenin; Autophagy
• ISSN: 0003-9861; 1096-0384; 1096-0384
• DOI: 10.1016/j.abb.2022.109121

Acute liver failure (ALF) is considered a fatal clinical disorder and novel therapeutic interventions are mandatory. 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 hepatoprotective effect and the possible underlying molecular mechanisms of naringenin in lipopolysaccharide (LPS)/D-galactosamine (D-Gal) mouse model of ALF. Interestingly, naringenin pretreatment substantially alleviated LPS/D-Gal-induced liver injury, enhanced survival, improved liver function and ameliorated histopathological 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-κB and NLRP3 pathways. Accordingly, apoptotic cell death provoked 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 hepatoprotective 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. [Display omitted] •Naringenin protected against LPS/D-Gal-induced acute liver failure (ALF) in mice.•Naringenin enhanced survival and improved histopathological alterations in ALF.•Naringenin suppressed NF-κB/NLRP3/IL-1β inflammatory pathway.•Naringenin alleviated oxidative and ER stress and repressed hepatic apoptosis.•Naringenin afforded hepatoprotection in LPS/D-Gal mice via promoting autophagy.