title: Ablation of dihydroceramide desaturase 1, a therapeutic target for the treatment of metabolic diseases, simultaneously stimulates anabolic and catabolic signaling.
abstract: The lipotoxicity hypothesis posits that obesity predisposes individuals to metabolic diseases because the oversupply of lipids to tissues not suited for fat storage leads to the accumulation of fat-derived molecules that impair tissue function. Means of combating this have been to stimulate anabolic processes to promote lipid storage or to promote catabolic ones to drive fat degradation. Herein, we demonstrate that ablating dihydroceramide desaturase 1 (Des1), an enzyme that produces ceramides, leads to the simultaneous activation of both anabolic and catabolic signaling pathways. In cells lacking Des1, the most common sphingolipids were replaced with dihydro forms lacking the double bond inserted by Des1. These cells exhibited a remarkably strong activation of the antiapoptotic and anabolic signaling pathway regulated by Akt/protein kinase B (PKB), were resistant to apoptosis, and were considerably larger than their wild-type counterparts. Paradoxically, Des1(-/-) cells exhibited high levels of autophagy. Mechanistic studies revealed that this resulted from impaired ATP synthesis due in part to decreased expression and activity of several complexes of the electron transport chain, particularly complex IV, leading to activation of AMP-activated protein kinase and its induction of the autophagosome. Thus, Des1 ablation enhanced starvation responses but dissociated them from the anabolic, prosurvival, and antiautophagic Akt/PKB pathways.
authors.affiliation: Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
authors.forename: Monowarul M
authors.initials: MM
authors.lastname: Siddique
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: Jianhong
authors.initials: J
authors.lastname: Ching
authors.forename: Mainak
authors.initials: M
authors.lastname: Mal
authors.forename: Olga
authors.initials: O
authors.lastname: Ilkayeva
authors.forename: Ya Jun
authors.initials: YJ
authors.lastname: Wu
authors.forename: Boon Huat
authors.initials: BH
authors.lastname: Bay
authors.forename: Scott A
authors.initials: SA
authors.lastname: Summers
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D049109:Cell Proliferation; D002518:Ceramides / Q000737:chemistry / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013107:Sphingolipids / Q000737:chemistry / Q000378:metabolism
chemical_list: D000596:Amino Acids; D002518:Ceramides; D008565:Membrane Proteins; D013107:Sphingolipids; D000255:Adenosine Triphosphate; D010088:Oxidoreductases; C108032:Degs protein, mouse; D051057:Proto-Oncogene Proteins c-akt
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