Pro-oxidant and proapoptotic effects of cholesterol oxidation products on human colonic epithelial cells: a potential mechanism of inflammatory bowel disease progression.
With the aim of investigating whether cholesterol oxidation products could contribute to the pathogenesis of the intestinal epithelial barrier dysfunction that occurs in human inflammatory bowel disease (IBD), differentiated versus undifferentiated CaCo-2 cells, an accepted model for human intestinal epithelial cells, were challenged with a dietary-representative mixture of oxysterols. Only differentiated colonic cells were susceptible to the proapoptotic action of the oxysterol mixture, checked both by enzymatic and by morphological methods, mainly because of a very low AKT phosphorylation pathway compared to the undifferentiated counterparts. Enhanced production of reactive oxygen species by a colonic NADPH oxidase hyperactivation seemed to represent the key event in oxysterol-induced up-regulation of the mitochondrial pathway of programmed death of differentiated CaCo-2 cells. These in vitro findings point to the pro-oxidant and cytotoxic potential of cholesterol oxidation products, of both dietary and endogenous origin, as an important mechanism of induction and/or worsening of the functional impairment of enteric mucosa that characterizes IBD.
Department of Clinical and Biological Sciences, University of Turin at San Luigi Gonzaga Hospital, 10043 Orbassano (Turin), Italy.
Fiorella
F
Biasi
Cinzia
C
Mascia
Marco
M
Astegiano
Elena
E
Chiarpotto
Mario
M
Nano
Barbara
B
Vizio
Gabriella
G
Leonarduzzi
Giuseppe
G
Poli
D017209:Apoptosis; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism* / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019610:Cytoprotection; D018450:Disease Progression; D004789:Enzyme Activation; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism* / Q000473:pathology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D019255:NADPH Oxidases / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D016877:Oxidants; D017382:Reactive Oxygen Species; D002784:Cholesterol; D019255:NADPH Oxidases; D051057:Proto-Oncogene Proteins c-akt