Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2013 May 17;28820:14463-14475. doi: 10.1074/jbc.M112.437210.
Show Gene links
Show Anatomy links
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
.
???displayArticle.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.
An,
Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance.
2004, Pubmed
An,
Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance.
2004,
Pubmed
Andersen,
A biotin switch-based proteomics approach identifies 14-3-3ζ as a target of Sirt1 in the metabolic regulation of caspase-2.
2011,
Pubmed
,
Xenbase
Arici,
Stimulation of proximal tubular cell apoptosis by albumin-bound fatty acids mediated by peroxisome proliferator activated receptor-gamma.
2003,
Pubmed
Bergeron,
Defects in regulation of apoptosis in caspase-2-deficient mice.
1998,
Pubmed
Bonzon,
Caspase-2-induced apoptosis requires bid cleavage: a physiological role for bid in heat shock-induced death.
2006,
Pubmed
Browning,
Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.
2004,
Pubmed
Canbay,
Fas enhances fibrogenesis in the bile duct ligated mouse: a link between apoptosis and fibrosis.
2002,
Pubmed
Cazanave,
Mechanisms and clinical implications of hepatocyte lipoapoptosis.
2010,
Pubmed
Coll,
Oleate reverses palmitate-induced insulin resistance and inflammation in skeletal muscle cells.
2008,
Pubmed
Danial,
Cell death: critical control points.
2004,
Pubmed
Dworkin,
Regulation of carbon flux from amino acids into sugar phosphates in Xenopus embryos.
1990,
Pubmed
,
Xenbase
Dworkin,
Carbon metabolism in early amphibian embryos.
1991,
Pubmed
,
Xenbase
El-Assaad,
Saturated fatty acids synergize with elevated glucose to cause pancreatic beta-cell death.
2003,
Pubmed
Feldstein,
Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.
2003,
Pubmed
Folbergrová,
Influence of complete ischemia on glycolytic metabolites, citric acid cycle intermediates, and associated amino acids in the rat cerebral cortex.
1974,
Pubmed
Frayn,
Adipose tissue as a buffer for daily lipid flux.
2002,
Pubmed
Fürstova,
Comparison of the effect of individual saturated and unsaturated fatty acids on cell growth and death induction in the human pancreatic beta-cell line NES2Y.
2008,
Pubmed
Gao,
Oleate protects against palmitate-induced insulin resistance in L6 myotubes.
2009,
Pubmed
Goldberg,
Effects of changes in brain metabolism on the levels of citric acid cycle intermediates.
1966,
Pubmed
Hardy,
Saturated fatty acid-induced apoptosis in MDA-MB-231 breast cancer cells. A role for cardiolipin.
2003,
Pubmed
Ho,
Caspase-2 is required for cell death induced by cytoskeletal disruption.
2008,
Pubmed
Hochachka,
Multiple end products of anaerobiosis in diving vertebrates.
1975,
Pubmed
Hu,
Differential regulation of dihydroceramide desaturase by palmitate versus monounsaturated fatty acids: implications for insulin resistance.
2011,
Pubmed
Ibrahim,
Mechanisms of lipotoxicity in NAFLD and clinical implications.
2011,
Pubmed
Imre,
Caspase-2 is an initiator caspase responsible for pore-forming toxin-mediated apoptosis.
2012,
Pubmed
Kim,
AMPK activator, AICAR, inhibits palmitate-induced apoptosis in osteoblast.
2008,
Pubmed
Kluck,
Cytochrome c activation of CPP32-like proteolysis plays a critical role in a Xenopus cell-free apoptosis system.
1997,
Pubmed
,
Xenbase
Kotarsky,
Metabolite profiles reveal energy failure and impaired beta-oxidation in liver of mice with complex III deficiency due to a BCS1L mutation.
2012,
Pubmed
Kusminski,
Diabetes and apoptosis: lipotoxicity.
2009,
Pubmed
Lewis,
Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes.
2002,
Pubmed
Li,
Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis.
1998,
Pubmed
Listenberger,
Triglyceride accumulation protects against fatty acid-induced lipotoxicity.
2003,
Pubmed
Listenberger,
Mechanisms of lipoapoptosis: implications for human heart disease.
2002,
Pubmed
Liu,
Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c.
1996,
Pubmed
Lupi,
Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated.
2002,
Pubmed
Malhi,
Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis.
2006,
Pubmed
Mei,
Differential roles of unsaturated and saturated fatty acids on autophagy and apoptosis in hepatocytes.
2011,
Pubmed
Miller,
Oleate prevents palmitate-induced cytotoxic stress in cardiac myocytes.
2005,
Pubmed
Mutomba,
Regulation of the activity of caspases by L-carnitine and palmitoylcarnitine.
2000,
Pubmed
Nutt,
Metabolic regulation of oocyte cell death through the CaMKII-mediated phosphorylation of caspase-2.
2005,
Pubmed
,
Xenbase
Nutt,
Metabolic control of oocyte apoptosis mediated by 14-3-3zeta-regulated dephosphorylation of caspase-2.
2009,
Pubmed
,
Xenbase
Ratziu,
A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis.
2012,
Pubmed
Sadagopan,
Circulating succinate is elevated in rodent models of hypertension and metabolic disease.
2007,
Pubmed
Selak,
Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase.
2005,
Pubmed
Smythe,
Systems for the study of nuclear assembly, DNA replication, and nuclear breakdown in Xenopus laevis egg extracts.
1991,
Pubmed
,
Xenbase
Staiger,
Saturated, but not unsaturated, fatty acids induce apoptosis of human coronary artery endothelial cells via nuclear factor-kappaB activation.
2006,
Pubmed
Taegtmeyer,
Metabolic responses to cardiac hypoxia. Increased production of succinate by rabbit papillary muscles.
1978,
Pubmed
Tu,
In situ trapping of activated initiator caspases reveals a role for caspase-2 in heat shock-induced apoptosis.
2006,
Pubmed
Unger,
Lipoapoptosis: its mechanism and its diseases.
2002,
Pubmed
Unger,
Lipid homeostasis, lipotoxicity and the metabolic syndrome.
2010,
Pubmed
Vastag,
Remodeling of the metabolome during early frog development.
2011,
Pubmed
,
Xenbase
Wieckowska,
Nonalcoholic fatty liver disease in the pediatric population: a review.
2005,
Pubmed
Wiesner,
Glutamate degradation in the ischemic dog heart: contribution to anaerobic energy production.
1989,
Pubmed
Witek,
Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis.
2009,
Pubmed
Yuzefovych,
Different effects of oleate vs. palmitate on mitochondrial function, apoptosis, and insulin signaling in L6 skeletal muscle cells: role of oxidative stress.
2010,
Pubmed
de Vries,
Saturated but not mono-unsaturated fatty acids induce apoptotic cell death in neonatal rat ventricular myocytes.
1997,
Pubmed