Fat accumulation in Caenorhabditis elegans triggered by the electrophilic lipid peroxidation product 4-hydroxynonenal (4-HNE).
Deposition and mobilization of fat in an organism are tightly controlled by multiple levels of endocrine and neuroendocrine regulation. Because these hormonal mechanisms ultimately act by affecting biochemical reactions of fat synthesis or utilization, obesity could be also modulated by altering directly the underlying lipid biochemistry. We have previously shown that genetically modified mice with an elevated level of the lipid peroxidation product 4-HNE become obese. We now demonstrate that the process is phylogenetically conserved and thus likely to be universal. In the nematode C. elegans, disruption of either conjugation or oxidation of 4-HNE leads to fat accumulation, whereas augmentation of 4-HNE conjugation results in a lean phenotype. Moreover, direct treatment of C. elegans with synthetic 4-HNE causes increased lipid storage, directly demonstrating a causative role of 4-HNE. The postulated mechanism, which involves modulation of acetyl-CoA carboxylase activity, could contribute to the triggering and maintenance of the obese phenotype on a purely metabolic level.
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Sharda P
SP
Singh
Maciej
M
Niemczyk
Ludwika
L
Zimniak
Piotr
P
Zimniak
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000444:Aldehyde Dehydrogenase / Q000235:genetics; D000447:Aldehydes / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000378:metabolism*; D019343:Citric Acid / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology*; D008054:Lipid Peroxides / Q000378:metabolism; D008316:Malonyl Coenzyme A / Q000378:metabolism; D010084:Oxidation-Reduction; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics; D034622:RNA Interference
D000447:Aldehydes; D005227:Fatty Acids; D008054:Lipid Peroxides; D019343:Citric Acid; D008316:Malonyl Coenzyme A; D000444:Aldehyde Dehydrogenase; D005982:Glutathione Transferase; D005978:Glutathione; C027576:4-hydroxy-2-nonenal