title: Thioredoxin-interacting protein deficiency disrupts the fasting-feeding metabolic transition.
abstract: Through a positional cloning approach, the thioredoxin-interacting protein gene (Txnip) was recently identified as causal for a form of combined hyperlipidemia in mice (Bodnar, J. S., A. Chatterjee, L. W. Castellani, D. A. Ross, J. Ohmen, J. Cavalcoli, C. Wu, K. M. Dains, J. Catanese, M. Chu, S. S. Sheth, K. Charugundla, P. Demant, D. B. West, P. de Jong, and A. J. Lusis. 2002. Positional cloning of the combined hyperlipidemia gene Hyplip1. Nat. Genet. 30: 110-116). We now show that Txnip-deficient mice in the fed state exhibit a metabolic profile similar to fasted mice, including increased levels of plasma ketone bodies and free fatty acids, decreased glucose, and increased hepatic expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and acyl-CoA oxidase. Dramatic differences in the expression of key metabolic enzymes were also observed in other tissues, and the fat-to-muscle ratio of Txnip-deficient mice was increased by approximately 40%. We demonstrate an effect of Txnip on the redox status, as the Txnip-deficient mice in the fed state had a significant increase in the ratio of NADH to NAD(+). Surprisingly, we observed that Txnip-deficient mice and wild-type mice had similar levels of thioredoxin activity, suggesting that the effects of Txnip deficiency may be mediated in part by other interactions. These results indicate a role for Txnip in the metabolic response to feeding and the maintenance of the redox status.
authors.affiliation: Department of Human Genetics, Medicine, Molecular Biology Institute, University of California, Los Angeles, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Sonal S
authors.initials: SS
authors.lastname: Sheth
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Castellani
authors.forename: Soumya
authors.initials: S
authors.lastname: Chari
authors.forename: Cory
authors.initials: C
authors.lastname: Wagg
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Thipphavong
authors.forename: Jackie S
authors.initials: JS
authors.lastname: Bodnar
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
authors.forename: Alan D
authors.initials: AD
authors.lastname: Attie
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001823:Body Composition; D002352:Carrier Proteins / Q000502:physiology*; D004798:Enzymes / Q000235:genetics; D005215:Fasting; D005247:Feeding Behavior; D008660:Metabolism; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D010641:Phenotype; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; D004798:Enzymes; C445672:Txnip protein, mouse; D013879:Thioredoxins