Fructose 1,6-bisphosphate reduced TNF-alpha-induced apoptosis in galactosamine sensitized rat hepatocytes through activation of nitric oxide and cGMP production.

Fructose 1,6-P2 (F1,6BP) protects rat liver against experimental hepatitis induced by galactosamine (GalN) by means of two parallel effects: prevention of inflammation, and reduction of hepatocyte sensitization to tumour necrosis factor-alpha (TNF-alpha). In a previous paper we reported the underlying mechanism involved in the prevention of inflammation. In the present study, we examined the intracellular mechanisms involved in the F1,6BP inhibition of the apoptosis induced by TNF-alpha in parenchyma cells of GalN-sensitized rat liver. We hypothesized that the increased nitric oxide (NO) production in livers of F1,6BP-treated rats mediates the antiapoptotic effect. This hypothesis was evaluated in cultured primary rat hepatocytes challenged by GalN plus tumour necrosis factor-alpha (GalN+TNF-alpha), to reproduce in vitro the injury associated with experimental hepatitis. Our results show a reduction in apoptosis concomitant with an increase in NO production and with a reduction in oxidative stress. In such conditions, guanylyl cyclase is activated and the increase in cGMP reduces the TNF-alpha-induced apoptosis in hepatocytes. These results provide new insights in the protective mechanism activated by F1,6BP and confirm its interest as a hepatoprotective agent.

Fructose 1,6-bisphosphate prevented endotoxemia, macrophage activation, and liver injury induced by D-galactosamine in rats.

OBJECTIVE: Fructose 1,6-bisphosphate (F1,6BP) protects organs against a wide range of challenges involving inflammation. We hypothesized that the primary action of F1,6BP is to prevent macrophage activation and cytokine release. Our aim was to determine the tissue and cellular targets for this bisphosphorylated sugar and to provide new insights into its mechanisms of action. DESIGN: Prospective, controlled laboratory study. SETTING: Animal resource facilities and research laboratory. SUBJECTS: Male Sprague-Dawley rats (200-250 g body weight). INTERVENTIONS: The protective action of F1,6BP was analyzed in galactosamine (GalN)-induced hepatitis in rats. The in vivo effects of F1,6BP were evaluated by changes in transaminase activities, blood endotoxins, and tumor necrosis factor (TNF)-alpha production in GalN-challenged rats. The targets of F1,6BP to reduce macrophage response to lipopolysaccharide (LPS) were determined by correlation between changes in TNF-alpha production and K+ fluxes through cell membrane in primary cultures of Kupffer cells. MEASUREMENTS AND MAIN RESULTS: The in vivo results indicate that F1,6BP treatment prevented GalN-induced injury in liver parenchymal cells. This protection was mainly associated with a reduction of the inflammatory response. F1,6BP prevention of GalN-induced endotoxemia correlated with preclusion of mast cell degranulation and histamine release that preceded the increased plasma endotoxins and liver production of TNF-alpha. In addition, F1,6BP treatment decreased sensitivity to LPS, which reduced the GalN-induced increase in TNF-alpha. The in vitro results show that F1,6BP inhibited Kupffer cell response and reduced TNF-alpha production by preventing LPS-induced K+ channel activation. CONCLUSIONS: The role of exogenous F1,6BP as a K+ channel modulator underlies its antihistaminic and anti-inflammatory action and increases its interest as a protective compound.