Thioredoxin binding protein-2/thioredoxin-interacting protein is a critical regulator of insulin secretion and peroxisome proliferator-activated receptor function.
The feeding-fasting nutritional transition triggers a dynamic change in metabolic pathways and is a model for understanding how these pathways are mutually organized. The targeted disruption of the thioredoxin binding protein-2 (TBP-2)/thioredoxin-interacting protein (Txnip)/VDUP1 gene in mice results in lethality with hypertriglyceridemia and hypoglycemia during fasting. To investigate the molecular mechanism of the nutritional transition and the role of TBP-2, microarray analyses were performed using the liver of TBP-2(-/-) mice in the fed and fasted states. We found that the fasting-induced reduction in the expression of lipogenic genes targeted by insulin (SREBP-1), such as FASN and THRSP, was abolished in TBP-2(-/-) mice, and the expression of lipoprotein lipase is down-regulated, which was consistent with the lipoprotein profile. TBP-2(-/-) mice also exhibited enhanced glucose-induced insulin secretion and sensitivity. Another feature of the hepatic gene expression in fed TBP-2(-/-) mice was the augmented expression of peroxisome proliferator activated receptor (PPAR) target genes, such as CD36, FABP2, ACOT1, and FGF21, to regulate fatty acid consumption. In TBP-2(-/-) mice, PPARalpha expression was elevated in the fed state, whereas the fasting-induced up-regulation of PPARalpha was attenuated. We also detected an increased expression of PPARgamma coactivator-1alpha protein in fed TBP-2(-/-) mice. TBP-2 overexpression significantly inhibited PPARalpha-mediated transcriptional activity induced by a specific PPARalpha ligand in vitro. These results suggest that TBP-2 is a key regulator of PPARalpha expression and signaling, and coordinated regulation of PPARalpha and insulin secretion by TBP-2 is crucial in the feeding-fasting nutritional transition.
Oka
Shin-ichi
S
Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Yoshihara
Eiji
E
Bizen-Abe
Akiko
A
Liu
Wenrui
W
Watanabe
Mutsumi
M
Yodoi
Junji
J
Masutani
Hiroshi
H
D000818:Animals; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D004435:Eating / Q000235:genetics; D005215:Fasting / Q000378:metabolism / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics* / Q000502:physiology*; D012727:Sex Characteristics; D013879:Thioredoxins / Q000235:genetics / Q000502:physiology*
D002352:Carrier Proteins; D007328:Insulin; D047492:Peroxisome Proliferator-Activated Receptors; C445672:Txnip protein, mouse; D013879:Thioredoxins