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Uncovering a Novel Role of the Apoptotic Initiator Caspase, Caspase-2

dc.contributor.advisor Kornbluth, Sally A Segear Johnson, Erika Lee 2014-05-14T19:16:47Z 2016-05-03T04:30:05Z 2014
dc.description.abstract <p>With the prevalence of obesity and metabolic syndrome rising sharply world-wide, it has become increasingly important to define the molecular mechanisms underlying the pathogenesis and progression of diseases associated with lipid-induced cytotoxicity. Cardiovascular disease, type-2 diabetes mellitus, and nonalchoholic fatty liver disease (NAFLD) have all recently gained recognition as diseases that are exacerbated by lipoapoptosis. In this dissertation, we demonstrate a novel role for caspase-2 as an initiator of lipoapoptosis. Using an unbiased metabolomics approach, 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. Metabolic treatments that block the buildup of LCFAs potently inhibit caspase-2, while add-back of a saturated LCFA restores caspase activation in the extract setting. Extending these findings to mammalian cells, we show that caspase-2 is engaged and activated in response to treatment with the saturated LCFA, palmitate. Down-regulation of caspase-2 significantly impairs cell death induced by saturated LCFAs, revealing a conserved, critical role for caspase-2 in mediating LCFA-induced lipoapoptosis. </p><p> Since lipoapoptosis has been implicated as a key driver of the progression of NAFLD, we aimed to determine the therapeutic significance of our findings by evaluating the importance of caspase-2 in an in vivo model of this disease. We subjected wild-type and caspase-2 knockout mice to a diet which induces severe liver steatosis and the development nonalcoholic steatohepatitis (NASH), the most advanced stage of NAFLD characterized by liver fibrosis. Interestingly, we observed an increase in caspase-2 protein levels in the livers of wild-type mice fed a NASH-inducing diet. These findings were of particular importance, since caspase-2 expression was also significantly elevated in patients diagnosed with NASH. Most importantly, we demonstrated that caspase-2 knockout mice are protected from apoptosis and fibrosis when fed a NASH-inducing diet, suggesting that caspase-2 is major regulator of hepatocyte lipoapoptosis. Together, these findings reveal a previously unknown role for caspase-2 as an initiator of lipoapoptosis and suggest that caspase-2 may be an attractive therapeutic target for inhibiting pathological lipid-induced apoptosis.</p>
dc.subject Biology
dc.subject Cellular biology
dc.subject Apoptosis
dc.subject Caspase-2
dc.subject Hepatocyte
dc.subject Lipids
dc.subject Metabolism
dc.subject Nonalcohohlic fatty liver disease
dc.title Uncovering a Novel Role of the Apoptotic Initiator Caspase, Caspase-2
dc.type Dissertation
dc.department Molecular Cancer Biology
duke.embargo.months 24

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