Thioredoxin-interacting protein deficiency disrupts the fasting-feeding metabolic transition

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-γ coactivator-1α, 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 ∼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. 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-γ coactivator-1α, 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 ∼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. We previously identified a naturally occurring mouse model for familial combined hyperlipidemia, a disorder characterized by increased plasma cholesterol and triglycerides (1Castellani L.W. Weinreb A. Bodnar J. Goto A.M. Doolittle M. Mehrabian M. Demant P. Lusis A.J. Mapping a gene for combined hyperlipidaemia in a mutant mouse strain.Nat. Genet. 1998; 18: 374-377Crossref PubMed Scopus (92) Google Scholar). Subsequently, positional cloning showed that the hyperlipidemia resulted from a spontaneous nonsense mutation in the gene for thioredoxin-interacting protein (Txnip), also known as vitamin D3 upregulated protein 1 (2Bodnar J.S. Chatterjee A. Castellani L.W. Ross D.A. Ohmen J. Cavalcoli J. Wu C. Dains K.M. Catanese J. Chu M. Sheth S.S. Charugundla K. Demant P. West D.B. Jong P. de Lusis A.J. Positional cloning of the combined hyperlipidemia gene Hyplip1.Nat. Genet. 2002; 30: 110-116Crossref PubMed Scopus (182) Google Scholar). Txnip was originally identified in a yeast two-hybrid screen for proteins that bind to thioredoxin (Txn), a thiol oxidoreductase that undergoes NADPH-dependent reduction and has multiple roles in intracellular signaling and resistance to oxidative stress (3Gasdaska J.R. Berggren M. Powis G. Cell growth stimulation by the redox protein thioredoxin occurs by a novel helper mechanism.Cell Growth Differ. 1995; 6: 1643-1650PubMed Google Scholar, 4Hirota K. Matsui M. Iwata S. Nishiyama A. Mori K. Yodoi J. AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1.Proc. Natl. Acad. Sci. USA. 1997; 94: 3633-3638Crossref PubMed Scopus (728) Google Scholar, 5Nakamura H. Nakamura K. Yodoi J. Redox regulation of cellular activation.Annu. Rev. Immunol. 1997; 15: 351-369Crossref PubMed Scopus (1001) Google Scholar, 6Ueda S. Nakamura H. Masutani H. Sasada T. Yonehara S. Takabayashi A. Yamaoka Y. Yodoi J. Redox regulation of caspase-3(-like) protease activity: regulatory roles of thioredoxin and cytochrome c.J. Immunol. 1998; 161: 6689-6695PubMed Google Scholar). The nonsense mutation in the hyperlipidemic mouse resulted in dramatically reduced mRNA levels and a truncated Txnip peptide the of the for (2Bodnar J.S. Chatterjee A. Castellani L.W. Ross D.A. Ohmen J. Cavalcoli J. Wu C. Dains K.M. Catanese J. Chu M. Sheth S.S. Charugundla K. Demant P. West D.B. Jong P. de Lusis A.J. Positional cloning of the combined hyperlipidemia gene Hyplip1.Nat. Genet. 2002; 30: 110-116Crossref PubMed Scopus (182) Google Scholar). We showed that Txnip-deficient mice increased of and ketone from Txnip-deficient mice also reduced hepatic suggesting an of the We that the Txnip deficiency reduced the fatty for triglycerides and ketone bodies (2Bodnar J.S. Chatterjee A. Castellani L.W. Ross D.A. Ohmen J. Cavalcoli J. Wu C. Dains K.M. Catanese J. Chu M. Sheth S.S. Charugundla K. Demant P. West D.B. Jong P. de Lusis A.J. Positional cloning of the combined hyperlipidemia gene Hyplip1.Nat. Genet. 2002; 30: 110-116Crossref PubMed Scopus (182) Google Scholar). the known of Txnip was to and we that the Txnip-deficient mice exhibit increased activity and an of the cellular redox in increased NADH to the of the (2Bodnar J.S. Chatterjee A. Castellani L.W. Ross D.A. Ohmen J. Cavalcoli J. Wu C. Dains K.M. Catanese J. Chu M. Sheth S.S. Charugundla K. Demant P. West D.B. Jong P. de Lusis A.J. Positional cloning of the combined hyperlipidemia gene Hyplip1.Nat. Genet. 2002; 30: 110-116Crossref PubMed Scopus (182) Google Scholar). Subsequently, Sheth S.S. Lusis A.J. and fatty to hepatic in hyperlipidemic PubMed Scopus Google to demonstrate that Txnip-deficient mice exhibit increased and increased hepatic and cholesterol Sheth S.S. Lusis A.J. thioredoxin-interacting protein cellular redox state to response to PubMed Scopus Google that fasted Txnip-deficient mice had levels and that the of by reduced the suggesting that increased may be a to the metabolic also that the resulted in part from increased expression of the Sheth S.S. Lusis A.J. thioredoxin-interacting protein cellular redox state to response to PubMed Scopus Google Scholar). J. T. oxidative stress of thioredoxin by thioredoxin-interacting PubMed Scopus Google that the oxidative stress to the of may be mediated in part by the of Txnip by increased We now metabolic of Txnip-deficient mice in the fed and fasted We observed in and in multiple the of significant differences in suggesting direct metabolic effects of Txnip in and the metabolic profile of fed Txnip-deficient mice that of mice to regulatory that to be is the transcriptional peroxisome proliferator-activated receptor-γ expression is increased in the Txnip-deficient mice in the fed We also the effects of Txnip We observed a significant increase of NADH in fed Txnip-deficient mice, an effect on the redox status, the activity of was results indicate that Txnip is for metabolic to The of the mutant mouse and were previously (1Castellani L.W. Weinreb A. Bodnar J. Goto A.M. Doolittle M. Mehrabian M. Demant P. Lusis A.J. Mapping a gene for combined hyperlipidaemia in a mutant mouse strain.Nat. Genet. 1998; 18: 374-377Crossref PubMed Scopus (92) Google Scholar, J.S. Chatterjee A. Castellani L.W. Ross D.A. Ohmen J. Cavalcoli J. Wu C. Dains K.M. Catanese J. Chu M. Sheth S.S. Charugundla K. Demant P. West D.B. Jong P. de Lusis A.J. Positional cloning of the combined hyperlipidemia gene Hyplip1.Nat. Genet. 2002; 30: 110-116Crossref PubMed Scopus (182) Google Scholar, P. for by PubMed Scopus Google Scholar). the effects of the Txnip mutation on mice were the of the for and of and were in of and on a an of were to and the in the fasted were an and were by the of ratio was The was to the Txnip-deficient and wild-type mice were in a and in the The of was as the of and were fed fasted for and were as the were as previously Castellani L.W. Lusis A.J. of mouse on plasma in PubMed Google Scholar). the of the were on to the and the we also free from the triglycerides between the was significant in that the increased in Txnip-deficient mice is to in of the ketone were in a were on and the were to to plasma were in a were in a were on and the to by levels were in by and levels were in a mouse were in of the were to an of and of of of were also to enzymes to as a was a of to the the were for and in a for and of the in was to a and in a The of and and to the of the on were as previously A. J.R. role for peroxisome proliferator-activated in the of reduced fatty and increased in the of mice of and reduced expression of 2002; PubMed Scopus Google Scholar). 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Yodoi J. of protein 1 as a of thioredoxin and PubMed Scopus Google to mouse and in also levels were as stress and effects on and in 2002; Scholar). of the of of mice, mice were as wild-type mice for that the were we the triglycerides in the mice in the The fasted in mice was and the in mice was were fed fasted for and were by was and in of was in of 1 was and for The was and The was a The was and to the a a The was as 1 and the for The was for for and for to The was 1 and the was an of and an of The reduction was as A. 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Txnip-deficient mice similar in to wild-type the of to is between the the fat-to-muscle ratio was in Txnip-deficient mice in wild-type mice was to a significant in the was by the in Txnip-deficient mice the metabolic profile of the Txnip-deficient mice, we and metabolic in the fed and fasted The Txnip-deficient mice increased levels of plasma ketone an increase wild-type mice in the fed state and a increase in the fasted state be increased in the fasted state as a of increased were increased in the fed and fasted in Txnip-deficient mice plasma levels were reduced in the fed and fasted the in the fasted state is in the fasted was also reduced in of the Txnip-deficient mice in the fasted state metabolic including increased ketone increased and decreased were observed in Txnip-deficient mice in the fed state is a in plasma levels in the fasted the Txnip-deficient mice the an increase in plasma triglycerides We previously also showed that Txnip-deficient mice exhibit decreased the in as by the of (2Bodnar J.S. Chatterjee A. Castellani L.W. Ross D.A. Ohmen J. Cavalcoli J. Wu C. Dains K.M. Catanese J. Chu M. Sheth S.S. Charugundla K. Demant P. West D.B. Jong P. de Lusis A.J. Positional cloning of the combined hyperlipidemia gene Hyplip1.Nat. Genet. 2002; 30: 110-116Crossref PubMed Scopus (182) Google fatty for fatty expression was also increased in Txnip-deficient and cholesterol levels were also in fasted Txnip-deficient mice metabolic between and is that the decreased to the metabolic observed in of Txnip-deficient the decreased and the decreased plasma levels were levels were by in the fed state of the Txnip-deficient mice The increased plasma the of ketone may be in part by a in by increased fatty acids, in to levels were in the fed and fasted Txnip-deficient mice, the levels to be increased in the fed and fasted the results of and the fed the in Txnip-deficient mice was the wild-type mice, had the fasted the Txnip-deficient mice had an of and the wild-type mice had an of plasma the of fatty to be the observed in Txnip-deficient previously (2Bodnar J.S. Chatterjee A. Castellani L.W. Ross D.A. Ohmen J. Cavalcoli J. Wu C. Dains K.M. Catanese J. Chu M. Sheth S.S. Charugundla K. Demant P. West D.B. Jong P. de Lusis A.J. Positional cloning of the combined hyperlipidemia gene Hyplip1.Nat. 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J. of hepatic the transcriptional PubMed Scopus Google Scholar). Txnip-deficient mice in the fed state showed a increase in expression wild-type mice in the fed state to wild-type mice an increase in in Txnip-deficient mice, expression was increased wild-type mice the known effects of on P. G. J. Wu J. G. J. of hepatic the transcriptional PubMed Scopus Google phosphoenolpyruvate and were increased and in the fed Txnip-deficient and were in the fasted state of the wild-type mice, in the Txnip-deficient mice, the expression was reduced to the fed state The expression of the in was in Txnip-deficient wild-type mice a in expression Txnip-deficient mice showed an increase the that Txnip-deficient mice exhibit a in response to feeding be in part by the expression of has that is regulated by and S. S. A. D. G. C. P. B. M. hepatic the PubMed Scopus Google Scholar). The of proteins the occurring the of and K. Matsui M. M. Y. T. K. Yodoi J. and thioredoxin and in PubMed Scopus Google Scholar). Txnip to a in the is that Txnip bind to other the increase in in the fed state is the of increased of we the protein levels of between Txnip-deficient and wild-type We observed significant in protein levels of between Txnip-deficient and wild-type in the fed state that the in expression may be occurring an We previously showed that Txnip-deficient mice triglycerides from the in increased plasma levels of and and (1Castellani L.W. Weinreb A. Bodnar J. Goto A.M. Doolittle M. Mehrabian M. Demant P. Lusis A.J. Mapping a gene for combined hyperlipidaemia in a mutant mouse strain.Nat. Genet. 1998; 18: 374-377Crossref PubMed Scopus (92) Google Scholar). is to increased fatty we the expression of in expression was in Txnip-deficient mice, expression was increased wild-type mice in fed and plasma triglycerides in Txnip-deficient mice increased the fed we the expression of enzymes in fatty The Txnip-deficient mice to increased expression of acyl-CoA is in in the fed and fasted the levels that show an increase in the activity of 1 in fasted Txnip-deficient mice, we observed an increase in the fed and fasted levels of mRNA A. M. Lusis A.J. between activity and plasma triglycerides in and mouse 2002; PubMed Scopus Google Scholar). has that is a key in the of fatty in the M. H. Y. P. of mice Natl. Acad. Sci. USA. 2002; PubMed Scopus Google Scholar). results increased expression of We also acyl-CoA an that the of fatty and is an that is upregulated T. C. in peroxisome proliferator-activated fatty the of hepatic in response to PubMed Scopus Google Scholar). wild-type mice, expression was increased Txnip-deficient mice, the was increased in the fed state wild-type mice the profile of Txnip-deficient mice similar to that of the fasted The in levels that may be of and Sheth S.S. Lusis A.J. thioredoxin-interacting protein cellular redox state to response to PubMed Scopus Google observed significant differences in levels between Txnip-deficient and wild-type mice in the fasted We levels in of mice in the fed and fasted an a was a increased levels of in the fed and fasted the differences were significant The increase in levels may be to the in the of the mice in the the mice in Sheth S.S. Lusis A.J. thioredoxin-interacting protein cellular redox state to response to PubMed Scopus Google Scholar). in resulted from expression of we the expression of in and in significant differences in were observed in the fed and fasted The expression of was also in is in is in response to and in P. Wu M. of to 1998; PubMed Scopus Google Scholar). We mRNA expression in from the the fed Txnip-deficient mice had decreased levels of mRNA wild-type mice, and in wild-type mice, mRNA levels The effect of Txnip deficiency on was by mRNA levels of and the fed the levels of in were decreased in Txnip-deficient The gene expression of and in the Txnip-deficient were from in the mRNA levels in the Txnip-deficient increased in the fasted the levels between the fed and fasted in the Txnip-deficient mRNA expression were also between the Txnip-deficient and of the Txnip-deficient mice were fed the levels in the were in the Txnip-deficient the levels increased that the Txnip deficiency has effects on the and the to and mRNA levels of in were between wild-type and Txnip-deficient mice response of to is an increased expression of is in the stimulation of A. of by in is for regulation of PubMed Scopus Google Scholar). Txnip-deficient mice, levels were in the fed state and the wild-type levels in the fasted state in as as fed Txnip-deficient mice an response to We also the expression of and in the expression in of the was by Txnip deficiency fed fasted levels in Txnip-deficient mice were decreased in the fed state and were in the fasted state is in fatty the of in the fasted Txnip-deficient mice is the observed increase in in the We previously that Txnip deficiency in increased levels of reduced and that in of the fatty for triglycerides (2Bodnar J.S. Chatterjee A. Castellani L.W. Ross D.A. Ohmen J. Cavalcoli J. Wu C. Dains K.M. Catanese J. Chu M. Sheth S.S. Charugundla K. Demant P. West D.B. Jong P. de Lusis A.J. Positional cloning of the combined hyperlipidemia gene Hyplip1.Nat. Genet. 2002; 30: 110-116Crossref PubMed Scopus (182) Google Scholar). we the levels of reduced and an stress and effects on and in 2002; Scholar). the and between the in the Txnip-deficient and wild-type the fed Txnip-deficient mice had a increase in the ratio of NADH to were significant differences observed between Txnip-deficient and wild-type mice in the fasted state The for were to the ratio The levels of NADH and and and and and that Txnip-deficient mice show a metabolic in the fed the in ratio to be to the metabolic of Txnip deficiency in the fasted that Txnip as a of activity and protein levels A. Matsui M. Iwata S. K. Masutani H. Nakamura H. Y. H. Y. Yodoi J. of protein 1 as a of thioredoxin and PubMed Scopus Google Scholar). activity was reduced by Txnip D3 in was a in activity A. Matsui M. Iwata S. K. Masutani H. Nakamura H. Y. H. Y. Yodoi J. of protein 1 as a of thioredoxin and PubMed Scopus Google Scholar). the of Txnip was in mutant mice and Txnip mRNA was we that mice exhibit expression and activity of in We the hepatic protein levels of in the fed and fasted The activity of was also in the fed and fasted by the of reduced in an as previously A. M. and thioredoxin 1995; PubMed Scopus Google Scholar). Surprisingly, the protein activity of were between Txnip-deficient mice and wild-type mice in the fed fasted These that the metabolic in Txnip-deficient mice may other as We previously positional cloning to Txnip as the gene in a naturally occurring mouse model (2Bodnar J.S. Chatterjee A. Castellani L.W. Ross D.A. Ohmen J. Cavalcoli J. Wu C. Dains K.M. Catanese J. Chu M. Sheth S.S. Charugundla K. Demant P. West D.B. Jong P. de Lusis A.J. Positional cloning of the combined hyperlipidemia gene Hyplip1.Nat. Genet. 2002; 30: 110-116Crossref PubMed Scopus (182) Google Scholar). We now in the metabolic from Txnip from Txnip deficiency results in a in the metabolic as as in a of the deficiency is in the expression of key metabolic enzymes and including expression of in and is an redox in the of Txnip-deficient mice, may be the the of the metabolic observed in Txnip-deficient the that activity was the of other interactions. The response to is increased of of fatty the and of fatty by and other tissues, be the increased and increased of ketone be by the and other as a of levels of and triglycerides in a fasted the fed Txnip-deficient mice exhibit of the of the fasted including increased ketone decreased and increased plasma The hepatic levels in the fasted Txnip-deficient mice be in part by a in the fed the Txnip-deficient mice a of in the fed the fasted levels M. H. Y. P. of mice Natl. Acad. Sci. USA. 2002; PubMed Scopus Google that deficiency to increased fatty and decreased decreased The increased expression and activity of in fasted Txnip-deficient mice that Txnip deficiency may the of fatty in the A. M. Lusis A.J. between activity and plasma triglycerides in and mouse 2002; PubMed Scopus Google Scholar). The of a significant in mRNA expression levels also that the to increased ketone and decreased in the Txnip-deficient occurs of The of fed Txnip-deficient mice also of a fasted in the Txnip-deficient mice had dramatically increased expression of in the fed state the Txnip-deficient the expression levels of metabolic as and were from levels observed in the Txnip-deficient of the regulatory in the response to is transcriptional is in and other in and P. G. J. Wu J. G. J. of hepatic the transcriptional PubMed Scopus Google Scholar, J. Y. P. M. of hepatic response by for in Natl. Acad. Sci. USA. PubMed Scopus Google Scholar, P. proliferator-activated 1 transcriptional and metabolic Rev. PubMed Scopus Google Scholar). is in in response to Txnip-deficient mice in the fed state had levels of fasted wild-type mice the known of as and also similar in expression levels identified Txnip as a key of Txnip expression is dramatically upregulated in to A. M. B. of of and a regulated signaling 2002; PubMed Scopus Google Scholar). glucose, Txnip occurs in the of that Txnip is a gene T. T. K. H. T. Y. and mRNA levels and gene expression in 2002; PubMed Scopus Google Scholar). showed that of Txnip-deficient mice reduced the in the fasted that the effects of Txnip mediated in part by levels Sheth S.S. Lusis A.J. thioredoxin-interacting protein cellular redox state to response to PubMed Scopus Google Scholar). Sheth S.S. Lusis A.J. thioredoxin-interacting protein cellular redox state to response to PubMed Scopus Google by in the fasted levels were increased in Txnip-deficient mice and that the of the was increased in fasted Txnip-deficient we observed a increased levels in fed and fasted were be in by the in the of the in and the for we and J. T. oxidative stress of thioredoxin by thioredoxin-interacting PubMed Scopus Google that the oxidative stress to the of may in part from the of Txnip by increased and other in that the hyperlipidemic of Txnip-deficient mice is in to increased from increased expression of fatty is mediated in part by increased expression of the key Sheth S.S. Lusis A.J. thioredoxin-interacting protein cellular redox state to response to PubMed Scopus Google Scholar). The to the reduced levels in fasted Txnip-deficient mice and of decreased hepatic increased by by increased plasma levels in the fed is increased The cellular redox state is for and we now that Txnip the levels of is to a metabolic reduced the of for in the J. M. Wu of and by the redox state of PubMed Scopus Google Scholar). is that an increased ratio the of to M. K. from is in of 1997; Google and that C. J. fatty and and in from PubMed Google Scholar). results show an increase in plasma and hepatic enzymes in the fed state of Txnip-deficient were significant in the of in the fasted the redox state the in fasted Txnip-deficient is that hepatic of were increased by in Txnip-deficient mice in the fasted state Sheth S.S. Lusis A.J. thioredoxin-interacting protein cellular redox state to response to PubMed Scopus Google Scholar). the Txnip deficiency the in results that the effects mediated by we to significant in levels in activity in Txnip-deficient We that Txnip may other of the including and of the by Txnip is to K. Matsui M. M. Y. T. K. Yodoi J. and thioredoxin and in PubMed Scopus Google Scholar, Y. D3 protein 1 oxidative stress the thioredoxin Immunol. PubMed Scopus Google Scholar). Yodoi and Y. Masutani H. Y. Y. K. Y. Yodoi J. 1 of PubMed Scopus Google a yeast two-hybrid screen to proteins that is the of Txnip the Y. Masutani H. Y. Y. K. Y. Yodoi J. 1 of PubMed Scopus Google Scholar). is that the nonsense mutation of Txnip we truncated has that of Txnip were for and of activity Y. D3 protein 1 oxidative stress the thioredoxin Immunol. PubMed Scopus Google Scholar). the nonsense mutation of Txnip occurs (2Bodnar J.S. Chatterjee A. Castellani L.W. Ross D.A. Ohmen J. Cavalcoli J. Wu C. Dains K.M. Catanese J. Chu M. Sheth S.S. Charugundla K. Demant P. West D.B. Jong P. de Lusis A.J. Positional cloning of the combined hyperlipidemia gene Hyplip1.Nat. Genet. 2002; 30: 110-116Crossref PubMed Scopus (182) Google the of Txnip is of the mRNA levels of the mutant Txnip were decreased (2Bodnar J.S. Chatterjee A. Castellani L.W. Ross D.A. Ohmen J. Cavalcoli J. Wu C. Dains K.M. Catanese J. Chu M. Sheth S.S. Charugundla K. Demant P. West D.B. Jong P. de Lusis A.J. Positional cloning of the combined hyperlipidemia gene Hyplip1.Nat. Genet. 2002; 30: 110-116Crossref PubMed Scopus (182) Google Scholar). results indicate that the in and fatty in response to feeding Txnip The to be mediated in part by effects on the redox of redox key and enzymes in the of and is is also that the redox is a a of of metabolic was by of and and by the of was in part by of

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