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XB-ART-46887
J Biol Chem 2013 May 17;28820:14463-14475. doi: 10.1074/jbc.M112.437210.
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Metabolomic profiling reveals a role for caspase-2 in lipoapoptosis.

Johnson ES , Lindblom KR , Robeson A , Stevens RD , Ilkayeva OR , Newgard CB , Kornbluth S , Andersen JL .


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The accumulation of long-chain fatty acids (LCFAs) in non-adipose tissues results in lipid-induced cytotoxicity (or lipoapoptosis). Lipoapoptosis has been proposed to play an important role in the pathogenesis of several metabolic diseases, including non-alcoholic fatty liver disease, diabetes mellitus, and cardiovascular disease. In this report, we demonstrate a novel role for caspase-2 as an initiator of lipoapoptosis. Using a metabolomics approach, we discovered that the activation of caspase-2, the initiator of apoptosis in Xenopus egg extracts, is associated with an accumulation of LCFA metabolites. Metabolic treatments that blocked the buildup of LCFAs potently inhibited caspase-2 activation, whereas adding back an LCFA in this scenario restored caspase activation. Extending these findings to mammalian cells, we show that caspase-2 was engaged and activated in response to treatment with the saturated LCFA palmitate. Down-regulation of caspase-2 significantly impaired cell death induced by saturated LCFAs, suggesting that caspase-2 plays a pivotal role in lipid-induced cytotoxicity. Together, these findings reveal a previously unknown role for caspase-2 as an initiator caspase in lipoapoptosis and suggest that caspase-2 may be an attractive therapeutic target for inhibiting pathological lipid-induced apoptosis.

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Species referenced: Xenopus laevis
Genes referenced: casp2

References [+] :
An, Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. 2004, Pubmed