Fructose prevents hypoxic cell death in liver

Abstract

Perfusion of livers from fasted rats with nitrogen-saturated buffer caused hepatocellular damage within 30 min. Lactate dehydrogenase (LDH) was released at maximal rates of approximately 300 U . g-1 . h-1 under these conditions, and virtually all cells in periportal and pericentral regions of the liver lobule were stained with trypan blue. Infusion of glucose, xylitol, sorbitol, or mannitol (20 mM) did not appreciably change the time course or extent of damage due to perfusion with nitrogen-saturated perfusate. However, fructose (20 mM) completely prevented damage assessed by LDH release, trypan blue uptake, and ultrastructural changes for at least 2 h of perfusion. Neither glucose, xylitol, sorbitol, nor mannitol (20 mM) increased lactate formation above basal levels during hypoxia. On the other hand, fructose (0.4-20 mM) caused a concentration-dependent increase in lactate formation that reached maximal rates of approximately 180 mumol . g-1 . h-1. The dose-dependent increase in glycolytic lactate production from fructose correlated well with cellular protection reflected by decreases in LDH release. ATP:ADP ratios were also increased from 0.4 to 1.8 in a dose-dependent manner by fructose. The results indicate that fructose protects the liver against hypoxic cell death by the glycolytic production of ATP in the absence of oxygen.

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

“…32 Fructose protection is generally attributed to glycolytic ATP formation and can be overcome through the activation of mitochondrial ATPases with an uncoupler. 30,31 Because a role for ATP in fructose protection against acetaminophen toxicity has been questioned, 40 we measured ATP in acetaminophen-exposed hepatocytes. Fructose plus glycine stabilized ATP levels and prevented acetaminophen-induced ATP depletion (see Fig.…”

“…Glycogen acts similarly to fructose in preventing anoxia and drug-induced ne- crotic cell killing of hepatocytes. 30 In vivo, glycogen may do the same by preventing necrotic cell killing or by converting oncotic necrosis to apoptosis, which is better tolerated.…”

Enhanced activity of the free radical producing enzyme xanthine oxidase in hypoxic rat liver. Regulation and pathophysiologic significance.

“…Fasting results in a variety ofchanges in hepatic metabolism, including depletion ofglycogen (14), decreased glutathione levels (32), and alteration ofthe hormonal milieu. Indeed, each of these variables has been implicated in the modulation of ischemic liver injury (14,33,34), although their relation to the conversion of XDH to XOD remains undefined. The relevance of our observations, is that it now shifts the focus in organ preservation to the physiological state (e.g., nutritional status) of the organ donor.…”

Intracellular pH during "chemical hypoxia" in cultured rat hepatocytes. Protection by intracellular acidosis against the onset of cell death.

“…5). The decrease of pHi was sustained for another [20][21][22][23][24][25][26][27][28][29][30] min. After a total of 30-40 min, pHi began to increase, and cell death followed shortly, as evidenced by leakage ofBCECF and coincident nuclear staining with propidium iodide (asterisk in Fig.…”

“…Intracellular acidosis developed rapidly in hepatocytes during ATP depletion and was sustained until shortly before cell death. Furthermore, intracellular acidosis tion using endogenous glycogen as a substrate, a factor that is otherwise quite difficult to control in hepatocytes (7,29). BCECF is well established as a fluorescent probe of intracellular pH (10,15,18).…”