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Caveolin-1 regulates mitochondrial cholesterol and hepatocellular susceptibility to TNF/FAS

Autor Marí, Montserrat ; Bosch, Marta; Fernández, Anna; Kassan, A.; Colell Riera, Anna ; Enrich, Carlos; García-Ruiz, Carmen ; Pol, Albert; Fernández-Checa, José C.
Fecha de publicación abr-2010
Citación Journal of Hepatology 52(Supl.1): S43-S44 (2010)
ResumenCaveolin-1 has been shown to function predominantly as a scaffolding protein involved in organizing the activity of multiple signalling molecules in caveolae. In addition, caveolin-1 exhibits binding properties towards fatty acids and cholesterol, suggesting it could play a role in the intracellular transport of lipids, including cholesterol. We have previously shown that caveolin-1 deficiency impairs liver regeneration, which is restored upon glucose supplementation, implying inefficient mitochondrialderived energy production. Caveolins can act independently of caveolae and are found in non-caveolar regions of caveolaecontaining cells including ER, Golgi and possibly mitochondria. Mitochondria can be closely apposed to plasma membrane caveolae and caveolin-1 has been detected in liver mitochondria. Since mitochondrial cholesterol modulates hepatocellular susceptibility to TNF/Fas, our aim was to examine the role of caveolin-1 in the regulation of mitochondrial cholesterol and fate of hepatocytes following TNF/Fas challenge. [Methods]: Primary hepatocytes and isolated mitochondria were prepared from wild-type and caveolin-1 knockout mice (KO). Oxygen consumption, GSH, free cholesterol levels, mitochondrial membrane permeabilization and subsequent release of cytochrome c and Smac/Diablo were analyzed in isolated mitochondria, while susceptibility to TNF/Fas-mediated apoptosis was examined in primary hepatocytes. [Results]: Impaired state 3 respiration and decreased acceptor control ratio were observed in mitochondria from caveolin-1 KO mice compared to wild-type mice. tBid+Bax-induced release of cytochrome c and Smac/Diablo was greater in isolated mitochondria from caveolin-1 KO mice than from wild-type mice. Moreover, these findings were accompanied by higher mitochondrial free cholesterol levels (30–50%) and GSH depletion (40–60%). Consistent with the latter results, hepatoyctes from caveolin-1 KO mice were more susceptible to Fas-mediated cytochrome c release and apoptosis with respect to wild-type mice, an outcome that was prevented upon GSH ethyl ester pretreatment. Finally, mitochondrial cholesterol extraction by methylcyclodextrin improved mitochondrial respiration and prevented tBid+Bax-mediated cytochrome c release. [Conclusions]: These findings indicate a novel role of caveolin-1 in the hepatocellular susceptibility to TNF/Fas-mediated apoptosis by regulating mitochondrial cholesterol trafficking and GSH homeostasis, implying that caveolin-1 could play a role in liver diseases, such as alcoholic and non-alcoholic steatohepatitis.
Descripción Trabajo presentado al 45th Annual Meeting of the European Association for the Study of the Liver (EASL) celebrado en Viena del 14 al 18 de abril de 2010.
URI http://hdl.handle.net/10261/92039
Identificadoresdoi: 10.1016/S0168-8278(10)60097-9
issn: 0168-8278
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