Published online before print August 21, 2009

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(American Journal of Pathology. 2009;175:1066-1076.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090071

Intestinal Glucose Uptake Protects Liver from Lipopolysaccharide and D-Galactosamine, Acetaminophen, and Alpha-Amanitin in Mice

Laura Zanobbio^*, Marco Palazzo^*, Silvia Gariboldi^*, Giuseppina F. Dusio^*, Diego Cardani^*, Valentina Mauro^*, Fabrizio Marcucci, Andrea Balsari^* and Cristiano Rumio^*

From the Italian Mucosal Immunity Laboratory,^* Department of Human Morphology and Biomedical Sciences "Città Studi," Università degli Studi di Milano, Milan; the Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute, Istituto Superiore di Sanità, Rome; and the Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy

We have recently observed that oral administration of D-glucose saves animals from lipopolysaccharide (LPS)-induced death. This effect is the likely consequence of glucose-induced activation of the sodium-dependent glucose transporter-1. In this study, we investigated possible hepatoprotective effects of glucose-induced, sodium-dependent, glucose transporter-1 activation. We show that oral administration of D-glucose, but not of either D-fructose or sucrose, prevents LPS-induced liver injury, as well as liver injury and death induced by an overdose of acetaminophen. In both of these models, physiological liver morphology is maintained and organ protection is confirmed by unchanged levels of the circulating markers of hepatotoxicity, such as alanine transaminase or lactate dehydrogenase. In addition, D-glucose was found to protect the liver from -amanitin-induced liver injury. In this case, in contrast to the previously described models, a second signal had to be present in addition to glucose to achieve protective efficacy. Toll-like receptor 4 stimulation that was induced by low doses of LPS was identified as such a second signal. Eventually, the protective effect of orally administered glucose on liver injury induced by LPS, overdose of acetaminophen, or -amanitin was shown to be mediated by the anti-inflammatory cytokine interleukin-10. These findings, showing glucose-induced protective effects in several animal models of liver injury, might be relevant in view of possible therapeutic interventions against different forms of acute hepatic injury.