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<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>
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