D-Galactosamine/Lipopolysaccharide-Induced Hepatotoxicity Downregulates Sirtuin 1 in Rat Liver: Role of Sirtuin 1 Modulation in Hepatoprotection

Abstract

D-Galactosamine/Lipopolysaccharide (D-GalN/LPS) is a well known model of hepatotoxicity that closely resembles acute liver failure (ALF) seen clinically. The role of sirtuin 1 in this model has not yet been documented. However, there have been a number of studies about the cytoprotective effects of resveratrol, a SIRT1 activator, in the liver. This study was aimed at elucidating the roles of SIRT1 protein expression or catalytic activity in D-GalN/LPS model of hepatotoxicity. ALF was induced in male Wistar rats by intraperitoneal injection of D-GalN and LPS. Some groups of animals were pretreated with resveratrol and/or EX-527 (SIRT1 inhibitor). The effects of these treatments were evaluated by biochemical and Western blot studies. D-GalN/LPS treatment was able to induce hepatotoxicity and significantly increase all markers of liver damage and lipid peroxidation. A dramatic decrease of SIRT1 levels in response to D-GalN/LPS treatment was also documented. Resveratrol pretreatment attenuated D-GalN/LPS-induced hepatotoxicity. EX-527 blocked the cytoprotective effects of resveratrol. However, both resveratrol and EX-527 pretreatments did not exhibit any significant effect on SIRT1 protein expression. Collectively, these results suggest that downregulation of SIRT1 expression is involved in the cytotoxic effects of D-GalN/LPS model and SIRT1 activity contributes to the cytoprotective effects of resveratrol in the liver.

An Antioxidant Combination Improves Histopathological Alterations and Biochemical Parameters in D-Galactosamine- Induced Hepatotoxicity in Rats

“…Administering D-GaIN generated free radicals that stimulated LPO. D-GalN in combination with lipopolysaccharide treatment induces hepatotoxicity and significantly increase all markers of liver injury and LPO (39). Several researchers have suggested that various compounds, such as flavonoids, lycopene, and magniferin, ameliorate D-GaIN-induced acute liver injury due to their antioxidant activities (40)(41)(42).…”

The angiotensin-converting enzyme inhibitor captopril rescues mice from endotoxin-induced lethal hepatitis

“…The liver injury induced by LPS/GalN in mice is a classical model widely used in experimental investigation of fulminant hepatitis. 27 The exposure to LPS/GalN stimulates a strong inflammatory response in the liver, and the liver injury largely depends on the excessive induction of the detrimental inflammatory mediators such as TNF-α. 28 The anti-inflammatory actions of ACEI have been well studied both in vitro and in vitro previously.…”

In Vitro and In Vivo Experimental Hepatotoxic Models in Liver Research: Applications to the Assessment of Potential Hepatoprotective Drugs

“…The combination of 10 µg/kg LPS with 400 mg/kg D-GalN produced a nonlethal hepatitis as proved histologically and biochemically evidenced by increases in ALT, AST, alpha-GST, NO, and the mRNA levels of the studied genes (Farghali et al 2009). Therefore, D-GalN/LPS combinations with different amounts of D-GalN/LPS appear very well reproducible model for in vivo experimental hepatitis studies , Kemelo et al 2014, Kemelo et al 2016. Moreover, a single dose of acetaminophen (APAP, 1 g/kg) was applied to rat to produce mild degree of hepatotoxicity (Wojnarova et al 2015).…”

“…The studies of Kemelo (Kemelo et al 2014, Kemelo et al 2016) reported that D-GalN/LPS-induced hepatotoxicity downregulates SIRT1 in rat liver and discussed the role of sirtuin 1 modulation in hepatoprotection. The role of sirtuin 1 in this model has not been documented before.…”