Cytoprotection by fructose and other ketohexoses during bile salt-induced apoptosis of hepatocytes

Abstract

sis or apoptosis. Necrosis is characterized by cell swelling Toxic bile salts cause hepatocyte necrosis at high conand autolysis with breakdown of the plasma membrane percentrations and apoptosis at lower concentrations. Almeability barrier. 4 In contrast, apoptosis is characterized by though fructose prevents bile salt-induced necrosis, the cell shrinkage, chromatin condensation, nuclear and DNA effect of fructose on bile salt-induced apoptosis is unfragmentation, and ultimately fragmentation of the cell into clear. Our aim was to determine if fructose also protects membrane-defined cell bodies referred to as apoptotic bodies. salt-induced necrosis and apoptosis would be of scientific by 0.2 U. However, extracellular acidification (pH 6.8),and clinical importance. Not only would an understanding of which decreased hepatocyte pH i 0.35 U and is known to the common mechanisms responsible for bile salt-induced inhibit necrosis, actually potentiated apoptosis 1.6-fold.necrosis and apoptosis provide basic information on the Fructose cytoprotection also could not be explained by mechanisms of cell death, but the information may also geninduction of bcl-2 transcription or metal chelation. Beerate strategies for the treatment of cholestatic liver diseases. cause we could not attribute fructose cytoprotection to Cytoprotective agents provide a unique paradigm with metabolic effects, alterations in the expression of bclwhich to help identify the common mechanisms responsible 2, or metal chelation, we next determined if the poorly for cell death. Cytoprotection by an agent against multiple metabolized ketohexoses, tagatose and sorbose, also inmodels or modes of cell death suggests common mechanisms hibited apoptosis; unexpectedly, both ketohexoses inare involved in the death process. Conversely, cytoprotection hibited apoptosis. Because bile salt-induced apoptosis in one model and a lack of protection in another model would and necrosis are inhibited by fructose, these data sugsuggest dissimilar mechanisms of cell death. We have demongest that similar processes initiate bile salt-induced hestrated that fructose, a cytoprotective agent in many models patocyte necrosis and apoptosis. In contrast, acidosis, of cell necrosis, prevents bile salt-induced necrosis of hepatowhich inhibits necrosis, potentiates apoptosis. Thus, ketohexose-sensitive pathways appear to initiate both bile cytes. 6 Fructose cytoprotection is thought to be mediated by salt-induced cell apoptosis and necrosis, whereas dis-glycolytic generation of adenosine triphosphate (ATP) or insimilar, pH-sensitive, effector mechanisms execute these tracellular acidification.9,10 However, the effect of fructose two different cell death processes. (HEPATOLOGY and its metabolic effects on cellular ATP and pH during bile 1997;25:81-86.) salt-induced apoptosis is unknown. Thus, the overall objective of this study was to determine if fructose also protects against bile salt-induced apoptosis. Our specific aims were The impairment of bile flow in chronic cholestatic liver ...

Reversibility of Caspase Activation and Its Role during Glycochenodeoxycholate-induced Hepatocyte Apoptosis

“…Pathophysiologically, ursodeoxycholate and its taurine-conjugated form are protective to hepatocytes by directly suppressing disruption of mitochondrial membrane structure (3), whereas glycochenodeoxycholate (GCDC) 1 is cytotoxic and contributes to hepatocellular injury (4). GCDC may cause hepatocyte damage by both acute necrosis and chronic apoptosis (5,6). GCDC-induced hepatocyte apoptosis includes death receptor and mitochondrial pathways (7,8).…”

Cycloprodigiosin hydrochloride, a new H+/Cl? symporter, induces apoptosis in human and rat hepatocellular cancer cell linesin vitro and inhibits the growth of hepatocellular carcinoma xenografts in nude mice

“…[1][2][3] The relationship between intracellular acidification and apoptosis has been studied. [4][5][6][7][8][9] In recent studies, the intracellular acidification may lead to activation of endonucleases and induce apoptosis in tumor cells. 6,8,9 In addition, the role of intracellular pH (pHi) in apoptosis and cell proliferation has been investigated.…”

Bile acids enhance the activity of the insulin receptor and glycogen synthase in primary rodent hepatocytes

“…[17][18][19][20] It should be noted, however, that 50 nM insulin is approximately 200 times higher than normal plasma insulin levels 40 but is within the range of insulin concentrations that are frequently used by laboratories for the culture of primary hepatocytes and other responsive cells, or for the in vitro activation of GS. 17,18,32,33,41 One potential explanation for the similarity of GS activation by insulin and bile acids in primary hepatocytes may be that the amplification of signaling occurs downstream of the receptor in such a way that a relatively small upstream activation of a receptor may cause a large activation of a downstream intracellular effector (e.g., AKT in Fig. 2C and D).…”