title: Cytoprotection by fructose and other ketohexoses during bile salt-induced apoptosis of hepatocytes.
abstract: Toxic bile salts cause hepatocyte necrosis at high concentrations and apoptosis at lower concentrations. Although fructose prevents bile salt-induced necrosis, the effect of fructose on bile salt-induced apoptosis is unclear. Our aim was to determine if fructose also protects against bile salt-induced apoptosis. Fructose inhibited glycochenodeoxycholate (GCDC)-induced apoptosis in a concentration-dependent manner with a maximum inhibition of 72% +/- 10% at 10 mmol/L. First, we determined if fructose inhibited apoptosis by decreasing adenosine triphosphate (ATP) and intracellular pH (pHi). Although fructose decreased ATP to <25% of basal values, oligomycin (an ATP synthase inhibitor) did not inhibit apoptosis despite decreasing ATP to similar values. Fructose (10 mmol/L) decreased intracellular pH (pHi) by 0.2 U. However, extracellular acidification (pH 6.8), which decreased hepatocyte pHi 0.35 U and is known to inhibit necrosis, actually potentiated apoptosis 1.6-fold. Fructose cytoprotection also could not be explained by induction of bcl-2 transcription or metal chelation. Because we could not attribute fructose cytoprotection to metabolic effects, alterations in the expression of bcl-2, or metal chelation, we next determined if the poorly metabolized ketohexoses, tagatose and sorbose, also inhibited apoptosis; unexpectedly, both ketohexoses inhibited apoptosis. Because bile salt-induced apoptosis and necrosis are inhibited by fructose, these data suggest that similar processes initiate bile salt-induced hepatocyte necrosis and apoptosis. In contrast, acidosis, which inhibits necrosis, potentiates apoptosis. Thus, ketohexose-sensitive pathways appear to initiate both bile salt-induced cell apoptosis and necrosis, whereas dissimilar, pH-sensitive, effector mechanisms execute these two different cell death processes.
authors.affiliation: Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Internal Medicine, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
authors.forename: I M
authors.initials: IM
authors.lastname: Zeid
authors.forename: S F
authors.initials: SF
authors.lastname: Bronk
authors.forename: P J
authors.initials: PJ
authors.lastname: Fesmier
authors.forename: G J
authors.initials: GJ
authors.lastname: Gores
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002614:Chelating Agents / Q000494:pharmacology; D005632:Fructose / Q000494:pharmacology*; D005999:Glycochenodeoxycholic Acid / Q000633:toxicity*; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002614:Chelating Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D005632:Fructose; D005999:Glycochenodeoxycholic Acid; D000255:Adenosine Triphosphate