Abstract
Simple SummaryPrevious studies from our laboratory have shown that chronic ethanol exposure-induced increase in apoptotic hepatocellular death is closely related to the ethanol-induced impairment in asialoglycoprotein receptor, a major component of liver sugar recognition system. The aim of this study was to examine whether the absence of this receptor confers increased susceptibility to fulminant liver failure induced by lipopolysaccharide/galactosamine. We further investigated whether treatment with betaine, a naturally occurring tertiary amine, prior to lipopolysaccharide/galactosamine injection is protective. Lipopolysaccharide/galactosamine injection caused a more pronounced liver damage in asialoglycoprotein receptor-deficient compared with the wild-type control mice. In addition, prior administration of betaine was found to significantly attenuate the lipopolysaccharide/galactosamine-induced increases in several liver injury parameters. Our work underscores the importance of normal functioning of asialoglycoprotein receptor in preventing severe liver damage and signifies a therapeutic role of betaine in prevention of liver injuries from toxin-induced fulminant liver failure.Background: Work from our laboratory has shown that the ethanol-induced increase in apoptotic hepatocellular death is closely related to the impairment in the ability of the asialoglycoprotein receptor (ASGP-R) to remove neighboring apoptotic cells. In this study, we assessed the role of ASGP-R in fulminant liver failure and investigated whether prior treatment with betaine (a naturally occurring tertiary amine) is protective. Methods: Lipopolysaccharide (LPS; 50 μg/kg BW) and galactosamine (GalN; 350 mg/kg BW) were injected together to wild-type and ASGP-R-deficient mice that were treated for two weeks prior with or without 2% betaine in drinking water. The mice were sacrificed 1.5, 3, or 4.5 h post-injection, and tissue samples were collected. Results: LPS/GalN injection generate distinct molecular processes, which includes increased production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), thus causing apoptosis as evident by increased caspase-3 activity. ASGP-R deficient animals showed increased liver caspase activities, serum TNF-α and IL-6 levels, as well as more pronounced liver damage compared with the wild-type control animals after intraperitoneal injection of LPS/GalN. In addition, prior administration of betaine was found to significantly attenuate the LPS/GalN-induced increases in liver injury parameters. Conclusion: Our work underscores the importance of normal functioning of ASGP-R in preventing severe liver damage and signifies a therapeutic role of betaine in prevention of liver injuries from toxin-induced fulminant liver failure.
Highlights
Fulminant liver failure results from massive hepatocyte death and severely impairs liver functions
Since hepatocellular apoptosis has been shown to be a major player in LPS/GalN injury, one of the aims of this study is to assess if the loss of asialoglycoprotein receptor (ASGP-R) makes these mice more susceptible than wild-type controls to LPS/GalN-induced fulminant liver failure
We show that betaine is effective in protecting against LPS-GalN-induced apoptosis in RD mice
Summary
Fulminant liver failure results from massive hepatocyte death and severely impairs liver functions. It has been shown that the metabolism of GalN leads to hepatotoxicity through inhibition of mRNA and protein synthesis; this occurs due to the concurrent accumulation of UDP-GalN derivatives and a depletion of hepatic UTP [11] This GalN “priming” leads to the potentiation of the toxic effects of LPS to produce typical hepatic cell injury followed by fulminant liver failure within 4–6 h of LPS/GalN administration [12,13]. GalN/TNF-α induces gap formation in endothelial cells, which allows PMNs to recognize apoptotic hepatocytes This is the trigger for PMN extravasation and attack on injured cells. Results: LPS/GalN injection generate distinct molecular processes, which includes increased production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), causing apoptosis as evident by increased caspase-3 activity. Conclusion: Our work underscores the importance of normal functioning of ASGP-R in preventing severe liver damage and signifies a therapeutic role of betaine in prevention of liver injuries from toxin-induced fulminant liver failure
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