title: Metabolomic profiling reveals a role for caspase-2 in lipoapoptosis.
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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27708.
authors.forename: Erika Segear
authors.initials: ES
authors.lastname: Johnson
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27708.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Lindblom
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27708.
authors.forename: Alexander
authors.initials: A
authors.lastname: Robeson
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27704; Department of Medicine, Duke University Medical Center, Durham, North Carolina 27708.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27704.
authors.forename: Olga R
authors.initials: OR
authors.lastname: Ilkayeva
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27708; Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27704.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27708. Electronic address: kornb001@mc.duke.edu.
authors.forename: Sally
authors.initials: S
authors.lastname: Kornbluth
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27708. Electronic address: jandersen@chem.byu.edu.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Andersen
mesh_terms: D000625:Aminooxyacetic Acid / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D053143:Caspase 2 / Q000378:metabolism*; D016923:Cell Death; D002850:Chromatography, Gel; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D055432:Metabolomics / Q000379:methods*; D010168:Palmitates / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014982:Xenopus laevis / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D010168:Palmitates; D034741:RNA, Small Interfering; C116917:acylcarnitine; D000625:Aminooxyacetic Acid; D053143:Caspase 2; D002331:Carnitine
keywords: Apoptosis; Caspase; Hepatocyte; Lipids; Metabolism
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