Abstract
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.
Highlights
Prior experiments described the metabolic regulation of caspase-2, but the underlying caspase-2-activating stimulus was unknown
We demonstrate a novel role for caspase-2 as an initiator of lipoapoptosis
We discovered that the activation of caspase-2, the initiator of apoptosis in Xenopus egg extracts, is associated with an accumulation of long-chain fatty acid (LCFA) metabolites
Summary
Prior experiments described the metabolic regulation of caspase-2, but the underlying caspase-2-activating stimulus was unknown. LCFA-induced lipoapoptosis has been shown to occur in many cell types, including hepatocytes, cardiomyocytes, proximal tubule cells in the kidney, and islet beta cells in the pancreas [7,8,9,10] These cells, which undergo apoptosis in response to treatment with saturated fatty acids, display several characteristic features of the intrinsic apoptotic pathway, including mitochondrial permeabilization, cytochrome c release, and effector caspase activation [11]. Caspase-2 activity was significantly increased following palmitate treatment, and downregulation of caspase-2 significantly impaired cell death induced by saturated LCFAs, revealing a conserved, critical role for caspase-2 in mediating LCFA-induced lipoapoptosis These findings may have clinical implications for the treatment of diseases associated with lipid accumulations
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