Key points are not available for this paper at this time.
The hepatocyte nuclear factor-4α (HNF-4α)/PGC-1 pathway plays a crucial role in the transcriptional regulation of hepatic gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase (PEPCK) and Glc-6-Pase, genes that are activated at fasting and suppressed in a fed state. SREBP-1c dominates the nutritional regulation of lipogenic genes inverse to gluconeogenesis. Here we show the mechanism by which SREBP-1 suppresses expression of gluconeogenic genes. A series of luciferase reporter assays demonstrated that SREBP-1a and -1c effectively inhibited the PEPCK promoter activity that was induced by HNF-4α. The HNF-4α-binding site in the glucocorticoid-response unit was responsible for the SREBP-1 inhibition, although SREBP-1 did not bind to the PEPCK promoter as demonstrated by electrophoretic mobility shift assays. The inhibitory effect was more potent in the isoform of SREBP-1a than SREBP-1c and was eliminated by deletion of the amino-terminal transactivation domain of SREBP-1. Coimmunoprecipitation experiments demonstrated that these two transcription factors directly interact through the transactivation domain of SREBP-1 and the ligand binding/AF2 domains of HNF-4α. Estimation of coactivator recruitment using HNF-4α-Gal4DBD fusion assay showed that SREBP-1 competitively inhibited PGC-1 recruitment, a requirement for HNF-4α activation. Consistent with these results, hepatic PEPCK and Glc-6-Pase mRNA levels are suppressed by overexpression of SREBP-1a and -1c in the transgenic mice. Our data indicate that SREBP-1 has a novel role as negative regulator of gluconeogenic genes through a cross-talk with HNF-4α interference with PGC-1 recruitment. The hepatocyte nuclear factor-4α (HNF-4α)/PGC-1 pathway plays a crucial role in the transcriptional regulation of hepatic gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase (PEPCK) and Glc-6-Pase, genes that are activated at fasting and suppressed in a fed state. SREBP-1c dominates the nutritional regulation of lipogenic genes inverse to gluconeogenesis. Here we show the mechanism by which SREBP-1 suppresses expression of gluconeogenic genes. A series of luciferase reporter assays demonstrated that SREBP-1a and -1c effectively inhibited the PEPCK promoter activity that was induced by HNF-4α. The HNF-4α-binding site in the glucocorticoid-response unit was responsible for the SREBP-1 inhibition, although SREBP-1 did not bind to the PEPCK promoter as demonstrated by electrophoretic mobility shift assays. The inhibitory effect was more potent in the isoform of SREBP-1a than SREBP-1c and was eliminated by deletion of the amino-terminal transactivation domain of SREBP-1. Coimmunoprecipitation experiments demonstrated that these two transcription factors directly interact through the transactivation domain of SREBP-1 and the ligand binding/AF2 domains of HNF-4α. Estimation of coactivator recruitment using HNF-4α-Gal4DBD fusion assay showed that SREBP-1 competitively inhibited PGC-1 recruitment, a requirement for HNF-4α activation. Consistent with these results, hepatic PEPCK and Glc-6-Pase mRNA levels are suppressed by overexpression of SREBP-1a and -1c in the transgenic mice. Our data indicate that SREBP-1 has a novel role as negative regulator of gluconeogenic genes through a cross-talk with HNF-4α interference with PGC-1 recruitment. Regulation of gluconeogenesis is crucial to maintain glucose homeostasis. Gluconeogenic genes such as phosphoenolpyruvate carboxykinase (PEPCK) 1The abbreviations used are: PEPCK, phosphoenolpyruvate carboxykinase; Glc-6-Pase, glucose-6-phosphatase; HNF-4α, hepatocyte nuclear factor-4α; EMSA, electrophoretic mobility shift assay; PPAR, peroxisome proliferator-activated receptor; LXR, liver X receptor; aa, amino acids; GST, glutathione S-transferase; DTT, dithiothreitol; LBD, ligand binding domain; SREBP, sterol regulatory element-binding protein; PBS, phosphate-buffered saline; GRU, glucocorticoid-response unit; SRE, sterol-response elements; RE, response element; TA, transactivation domain. and glucose-6-phosphatase (Glc-6-Pase) are nutritionally regulated in the liver at the transcriptional level, are highly activated during fasting or starvation, and are suppressed in a fed state. PEPCK promoter has been extensively studied and shown to be induced by several hormonal stimuli (glucocorticoid, glucagons, and thyroid hormone) and transcriptional factors (cAMP-response element-binding protein, C/EBPα, HNF-3, HNF-4α, and PPARα) (1Hanson R.W. Reshef L. Annu. Rev. Biochem. 1997; 66: 581-611Crossref PubMed Scopus (634) Google Scholar). Among these, insulin is a dominant negative regulator of PEPCK promoter through several pathways (1Hanson R.W. Reshef L. Annu. Rev. Biochem. 1997; 66: 581-611Crossref PubMed Scopus (634) Google Scholar). Hepatocyte nuclear factor-4α (HNF-4α) is a highly conserved member of the nuclear receptor superfamily and was initially identified as a transcriptional factor required for liver-specific gene expression (2Sladek F.M. Zhong W.M. Lai E. Darnell Jr., J.E. Genes Dev. 1990; 4: 2353-2365Crossref PubMed Scopus (861) Google Scholar), although it is also expressed in kidney, intestine, and pancreas (3Drewes T. Senkel S. Holewa B. Ryffel G.U. Mol. Cell. Biol. 1996; 16: 925-931Crossref PubMed Scopus (192) Google Scholar). Recently, HNF-4α and a coactivator, peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1), have been shown to activate expression of PEPCK (4Hall R.K. Sladek F.M. Granner D.K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 412-416Crossref PubMed Scopus (199) Google Scholar) and Glc-6-Pase (5Rajas F. Gautier A. Bady I. Montano S. Mithieux G. J. Biol. Chem. 2002; 277: 15736-15744Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar) by binding to HNF-4α-binding cis-elements in their promoters. Crucial roles of HNF-4α and PGC-1 in nutritional regulation of these genes, and thus gluconeogenesis, were confirmed by analysis of liver-specific HNF-4α knockout mice and by adenovirus-mediated overexpression of PGC-1 in mouse livers (6Rhee J. Inoue Y. Yoon J.C. Puigserver P. Fan M. Gonzalez F.J. Spiegelman B.M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 4012-4017Crossref PubMed Scopus (476) Google Scholar, 7Yoon J.C. Puigserver P. Chen G. Donovan J. Wu Z. Rhee J. Adelmant G. Stafford J. Kahn C.R. Granner D.K. Newgard C.B. Spiegelman B.M. Nature. 2001; 413: 131-138Crossref PubMed Scopus (1528) Google Scholar). The sterol regulatory element-binding protein (SREBP) family has been established as a group of transcription factors regulating transcription of genes involved in cholesterol and fatty acid synthesis. SREBP proteins are initially bound to the rough endoplasmic reticulum membrane and form a complex with SREBP cleavage-activating protein (SCAP), a sterol-sensing molecule. Upon sterol deprivation, SREBP is cleaved to liberate the amino-terminal portion, containing a basic helix-loop-helix leucine zipper domain, and enters the nucleus where it can bind to specific sterol-response elements (SRE) in the promoters of target genes (8Brown M.S. Goldstein J.L. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 11041-11048Crossref PubMed Scopus (1110) Google Scholar, 9Brown M.S. Goldstein J.L. Cell. 1997; 89: 331-340Abstract Full Text Full Text PDF PubMed Scopus (3029) Google Scholar, 10Brown M.S. Ye J. Rawson R.B. Goldstein J.L. Cell. 2000; 100: 391-398Abstract Full Text Full Text PDF PubMed Scopus (1151) Google Scholar). Three isoforms of SREBP-1a, -1c, and -2 are known. Although SREBP-2 plays a crucial role in regulation of cholesterol synthesis, SREBP-1c controls gene expression of lipogenic enzymes (11Horton J.D. Goldstein J.L. Brown M.S. J. Clin. Investig. 2002; 109: 1125-1131Crossref PubMed Scopus (3838) Google Scholar, 12Shimano H. Trends Cardiovasc. Med. 2000; 10: 275-278Crossref PubMed Scopus (68) Google Scholar, 13Shimano H. Prog. Lipid Res. 2001; 40: 439-452Crossref PubMed Scopus (587) Google Scholar, 14Shimano H. Vitam. Horm. 2002; 65: 167-194Crossref PubMed Google Scholar). Insulin and glucose have been well known to stimulate lipogenesis, presumably through induction of SREBP-1c expression of which is highly nutritionally regulated in the liver and adipose tissue. Recently, we reported (15Yoshikawa T. Ide T. Shimano H. Yahagi N. Amemiya-Kudo M. Matsuzaka T. Yatoh S. Kitamine T. Okazaki H. Tamura Y. Sekiya M. Takahashi A. Hasty A.H. Sato R. Sone H. Osuga J.I. Ishibashi S. Yamada N. Mol. Endocrinol. 2003; 7: 1240-1254Crossref Scopus (216) Google Scholar, 16Ide T. Shimano H. Yoshikawa T. Yahagi N. Amemiya-Kudo M. Matsuzaka T. Nakakuki M. Yatoh S. Iizuka Y. Tomita S. Ohashi K. Takahashi A. Sone H. Gotoda T. Osuga J.I. Ishibashi S. Yamada N. Mol. Endocrinol. 2003; 7: 1255-1267Crossref Scopus (148) Google Scholar) that cross-talk between PPARs and LXRs could be involved in reciprocal nutritional regulation of fatty acid metabolism. Considering the physiologically related roles of gluconeogenesis and lipogenesis, their transcriptional regulators HNF-4α and SREBP-1c could reciprocally regulate their target genes. In fact, fasting/feeding response to and insulin/glucose effect on these factors are completely opposite. Despite this knowledge, a mutual interaction between these two pathways has never been explored. Here we investigate the effects of SREBPs on the HNF-4α/PGC-1 pathway, and we examine the potential role of SREBPs in the regulation of gluconeogenesis. Animals—SREBP transgenic mice used in this study were described previously (17Shimano H. Horton J.D. Hammer R.E. Shimomura I. Brown M.S. Goldstein J.L. J. Clin. Investig. 1996; 98: 1575-1584Crossref PubMed Scopus (699) Google Scholar, 18Shimano H. Horton J.D. Shimomura I. Hammer R.E. Brown M.S. Goldstein J.L. J. Clin. Investig. 1997; 99: 846-854Crossref PubMed Scopus (688) Google Scholar). Mice were housed in colony cages and maintained on a 12-h light/12-h dark cycle. Before time of killing, transgenic animals and littermate controls were placed on the low carbohydrate/high protein diet for 1 week to induce expression of the transgene. Mice were killed after a 12-h fast. were by using A series of were by the PEPCK promoter to to or to by the The HNF-4α containing of elements was by the of of the PEPCK to a luciferase gene The expression for SREBP-1a, -1c, and -2 were as described previously H. Yahagi N. Amemiya-Kudo M. Hasty A.H. Osuga J. Tamura Y. F. Iizuka Y. Ohashi K. K. Gotoda T. Ishibashi S. Yamada N. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). SREBP-1 expression was by SREBP-1 The expression for mouse PGC-1 was by The expression for mouse HNF-4α was by The expression for fusion protein was by HNF-4α of in the The expression for HNF-4α was by HNF-4α of the on The expression for SREBP-1a was by the of the nuclear form of SREBP-1a The expression for or were by the The expression for the HNF-4α were by the The expression for and were a T. were by mouse livers was with of mice were to for mouse PEPCK, Glc-6-Pase, and were of mouse liver with the and for and for and and for was used as for PGC-1 and HNF-4α. was with the for mouse PEPCK, Glc-6-Pase, HNF-4α, PGC-1 and with using the were with for at with two were by and were at in of in containing amino for 1 and with Before were in at a of or in at a of were with to the The of was to in or in with protein A was to after of was used as a or of were with phosphate-buffered and assays were to the with assay and luciferase activity was by using the luciferase was also to for experiments were in and fusion proteins were expressed in and using using to the in were at to of induction with at for were and in A 1 DTT, The were on by and at for at The was for at for 1 on a with that were in A. were with A. or fusion proteins were with at for The and of and fusion proteins were by and using a known of the were at assays were proteins were by using or fusion proteins were with for 1 at and a of or fusion were with HNF-4α or PGC-1 in binding 1 1 for at or were extensively with containing or or fusion proteins were with at for and proteins were by and were and with were at in of in containing and with were with the expression for and by using Before of was to the as a of were on and nuclear proteins were as described previously H. Yahagi N. Amemiya-Kudo M. Hasty A.H. Osuga J. Tamura Y. F. Iizuka Y. Ohashi K. K. Gotoda T. Ishibashi S. Yamada N. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). were for 1 at with and at with protein the were with containing and on by analysis was by using and SREBP-1a and HNF-4α proteins were using the were by of the in by to for and to The were by using the of E. in the of The binding of were in binding 1 1 with and of and were for 1 at and on in at for 1 at were by to the used were for HNF-4α and for SREBP-1 were by The for is as PEPCK site and SREBP the of HNF-4α by the of genes by we identified the PEPCK gene by analysis of liver SREBP-1a transgenic and mice. The hepatic expression of PEPCK was by SREBP-1a was with the that adenovirus-mediated overexpression of SREBP-1c in mRNA of PEPCK gene induced by and K. P. P. M. P. F. R.W. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The glucocorticoid-response unit has been as a to regulate PEPCK gene transcription by between receptor and transcriptional factors in the liver the glucocorticoid-response and is the binding site of HNF-4α and is responsible for HNF-4α of the PEPCK promoter (4Hall R.K. Sladek F.M. Granner D.K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 412-416Crossref PubMed Scopus (199) Google Scholar). investigate the role of SREBP as a regulator of PEPCK promoter we SREBP could the PEPCK promoter in by using a luciferase reporter gene to the PEPCK promoter containing shown in HNF-4α expression induction of PEPCK promoter The HNF-4α transactivation of the PEPCK promoter was by of a protein A presumably to protein A of element-binding protein, PEPCK through the site of SREBPs in a of the PEPCK promoter activity induced by HNF-4α and Among the isoforms of SREBP-1a and -2 the inhibitory effect than The is to the amino-terminal transactivation domain of SREBP-1c as with that of SREBP-1a the amino-terminal transactivation domain of SREBP-1 was the SREBP-1 inhibitory effect on the PEPCK promoter was completely although this binding activity to the sterol regulatory that the amino-terminal transactivation domain of SREBP is for the of PEPCK promoter shown the PEPCK promoter activity induced by HNF-4α was also by SREBPs in a data that inhibitory of SREBPs on PEPCK expression is transcriptional through interference with HNF-4α activation. of PEPCK by SREBPs through the responsible for the inhibitory effect of SREBP on HNF-4α, a series of PEPCK promoter was for in In the of GRU, luciferase activity was than by HNF-4α, and the of the to the HNF-4α which is with the that the for HNF-4α is the site in a HNF-4α induction in this which is presumably to site The HNF-4α as in luciferase was suppressed by of completely this SREBP that is for the inhibitory effect of SREBP on HNF-4α of the PEPCK in for the of SREBP on could as a negative regulator of transcription by binding to the as reported for the promoter of protein R. Inoue J. T. T. M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). in the were identified in the of the PEPCK promoter demonstrated that SREBP-1a did not bind to the of the PEPCK HNF-4α bound to this the that SREBPs PEPCK promoter through their SREBP a of HNF-4α we on the in as SREBP The containing was for these of HNF-4α by HNF-4α was by PGC-1 in a and is with the that PGC-1 is coactivator of HNF-4α J.C. Puigserver P. Chen G. Donovan J. Wu Z. Rhee J. Adelmant G. Stafford J. Kahn C.R. Granner D.K. Newgard C.B. Spiegelman B.M. Nature. 2001; 413: 131-138Crossref PubMed Scopus (1528) Google Scholar). shown in SREBP-1a and SREBP-1c this HNF-4α data the potential for a interaction between HNF-4α and SREBP in this SREBP with HNF-4α in and in this we used assays with fusion proteins and in HNF-4α as the shown and not GST, were to HNF-4α. indicate that SREBP-1 could bind HNF-4α in The amino-terminal of SREBP-1a was also to HNF-4α. data the that the amino-terminal of SREBP-1 is responsible for inhibitory effect on HNF-4α. the the interaction between SREBP-1a and PGC-1 could not be as shown in of interaction the of between HNF-4α and SREBP-1 in PGC-1 recruitment as a mechanism for SREBP-1 of HNF-4α to the binding in HNF-4α to SREBP, we expression for domains of HNF-4α. shown in protein the ligand binding domain and of HNF-4α with the amino-terminal and binding domains of HNF-4α did not bind to The showed a to the of HNF-4α. data that the binding of these two is through interaction between the domain of SREBP and domains of HNF-4α. the interaction between SREBP-1a and HNF-4α was confirmed in as shown in was to in SREBP with PGC-1 for of the interaction between SREBP-1 and HNF-4α, two for the mechanism of the SREBP inhibitory effect on the PEPCK promoter could be interaction the of HNF-4α to bind to or it with the recruitment of PGC-1 by HNF-4α. examine the we by using in the PEPCK promoter as a shown in A and the binding of HNF-4α to was not by of SREBP-1a or PGC-1 at the to SREBP-1 has inhibitory effect on the interaction between HNF-4α and a assay for of the recruitment of PGC-1 by HNF-4α was HNF-4α and domain were to the of of coactivator recruitment PGC-1 and not or as coactivator for HNF-4α that PGC-1 HNF-4α and that SREBP-1a and SREBP-1c competitively the luciferase In the amino-terminal SREBP inhibitory effect on this indicate that SREBP-1 effectively the interaction between HNF-4α and PGC-1 through the amino-terminal of SREBP-1. In this inhibition, SREBP-1a was more than recruitment and of HNF-4α was inhibited by of fusion protein expression and containing of of HNF-4α protein was to binding domain for of PGC-1 recruitment and of HNF-4α. of HNF-4α by in were with expression for fusion protein and or were after of activity was and by luciferase SREBP of PGC-1 in were with expression for fusion protein PGC-1 and and SREBP-1a, or were after of activity was and by luciferase experiments were in SREBP-1 with PGC-1 in of SREBP-1a the HNF-4α activity more than for the PGC-1 recruitment were between SREBP-1a and -1c in the was at of that SREBP-1a has a in the than SREBP-1c investigate the between SREBP-1 and PGC-1 on of HNF-4α the by SREBP-1a was also with of PGC-1 in shown PGC-1 competitively HNF-4α by SREBP-1a in a it could be that SREBP-1 can with PGC-1 in HNF-4α through SREBP-1 and HNF-4α of SREBP-1 of Gluconeogenic Genes in the series of in and experiments shown that SREBP the PEPCK investigate the of SREBP-1 on PEPCK expression in livers of transgenic mice SREBP-1a and -1c were analysis demonstrated that the hepatic PEPCK mRNA as in mice at fasting was by overexpression of SREBP-1a and -1c the mRNA of Glc-6-Pase, HNF-4α target gene involved in hepatic glucose was also in these transgenic mice. of HNF-4α and genes was not by SREBP-1 the that SREBP-1 gluconeogenic genes in presumably through interference with PGC-1 recruitment to HNF-4α. study that SREBP HNF-4α in the induction of PEPCK promoter A series of reporter EMSA, and coactivator recruitment indicate that the SREBP is through interaction with HNF-4α, to recruitment of The interaction is through the of SREBP and the site of HNF-4α. has been shown that the of SREBPs transcriptional activity of the SREBP SREBP-1c with the has a transactivation potential for SREBP target genes as with SREBP-1a and -2 with (17Shimano H. Horton J.D. Hammer R.E. Shimomura I. Brown M.S. Goldstein J.L. J. Clin. Investig. 1996; 98: 1575-1584Crossref PubMed Scopus (699) Google Scholar, 18Shimano H. Horton J.D. Shimomura I. Hammer R.E. Brown M.S. Goldstein J.L. J. Clin. Investig. 1997; 99: 846-854Crossref PubMed Scopus (688) Google Scholar). is that SREBP-1c was in of HNF-4α to for The in for SREBP-1a and -1c and of activity in SREBP this Our data indicate that the protein interaction between HNF-4α and SREBP PGC-1 recruitment for HNF-4α and not HNF-4α binding to Considering that PGC-1 has been reported to bind to the domain of HNF-4α J.C. Puigserver P. Chen G. Donovan J. Wu Z. Rhee J. Adelmant G. Stafford J. Kahn C.R. Granner D.K. Newgard C.B. Spiegelman B.M. Nature. 2001; 413: 131-138Crossref PubMed Scopus (1528) Google Scholar), of and not of HNF-4α as site can the mechanism of The of is to be a between SREBP-1a and the study of SREBP-1 and it is also that binding of SREBP to the of HNF-4α could the of to HNF-4α, in of PGC-1 recruitment. HNF-4α ligand and the mechanism for HNF-4α by the are although analysis of the of HNF-4α indicate that the HNF-4α ligand could be S. K. M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). fatty have been reported to regulate the transcription of Glc-6-Pase through the of HNF-4α activity in (5Rajas F. Gautier A. Bady I. Montano S. Mithieux G. J. Biol. Chem. 2002; 277: 15736-15744Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). it is that SREBP binding to HNF-4α HNF-4α through of these potential or In the livers of SREBP-1a and -1c transgenic mRNA levels of gluconeogenic PEPCK and Glc-6-Pase, were expression of Glc-6-Pase as well as PEPCK to be regulated by the HNF-4α/PGC-1 pathway (6Rhee J. Inoue Y. Yoon J.C. Puigserver P. Fan M. Gonzalez F.J. Spiegelman B.M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 4012-4017Crossref PubMed Scopus (476) Google Scholar, 7Yoon J.C. Puigserver P. Chen G. Donovan J. Wu Z. Rhee J. Adelmant G. Stafford J. Kahn C.R. Granner D.K. Newgard C.B. Spiegelman B.M. Nature. 2001; 413: 131-138Crossref PubMed Scopus (1528) Google Scholar) with adenovirus-mediated overexpression of PGC-1 and liver-specific HNF-4α knockout mice. with on SREBP of the HNF-4α/PGC-1 pathway, SREBPs could be involved in regulation of gluconeogenesis through of gluconeogenic genes. a in could a role in regulation of gluconeogenesis, it is highly induced in a fed for after the of as shown in J.D. Y. Shimomura I. Shimano H. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). SREBP-1c of gluconeogenesis could hepatic glucose hepatic glucose for in a SREBP-1c expression was completely suppressed N. Shimano H. Hasty A.H. Amemiya-Kudo M. Okazaki H. Tamura Y. Iizuka Y. F. Ohashi K. Osuga J. K. Gotoda T. R. Ishibashi S. Yamada N. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, T. Shimano H. Yahagi N. Ide T. Amemiya-Kudo M. Matsuzaka T. Nakakuki M. Tomita S. Okazaki H. Tamura Y. Iizuka Y. Ohashi K. Takahashi A. Sone H. Osuga J. Gotoda T. Ishibashi S. Yamada N. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar) gluconeogenesis to be for the of glucose homeostasis. Recently, of ligand glucose in a of and insulin In mice with of PEPCK and Glc-6-Pase were as with that of mice. we and T. Shimano H. Yoshikawa T. Yahagi N. Amemiya-Kudo M. Matsuzaka T. Nakakuki M. Yatoh S. Iizuka Y. Tomita S. Ohashi K. Takahashi A. Sone H. Gotoda T. Osuga J.I. Ishibashi S. Yamada N. Mol. Endocrinol. 2003; 7: 1255-1267Crossref Scopus (148) Google Scholar, T. Shimano H. Amemiya-Kudo M. Yahagi N. Hasty A.H. Matsuzaka T. Okazaki H. Tamura Y. Iizuka Y. Ohashi K. Osuga J. K. Gotoda T. S. Ishibashi S. Yamada N. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar) demonstrated previously that the transcription of SREBP-1c is induced through in and in it could be that of gluconeogenic genes by the ligand could be through a in we reported that cross-talk between PPARs and LXRs could be involved in reciprocal nutritional regulation of fatty acid (15Yoshikawa T. Ide T. Shimano H. Yahagi N. Amemiya-Kudo M. Matsuzaka T. Yatoh S. Kitamine T. Okazaki H. Tamura Y. Sekiya M. Takahashi A. Hasty A.H. Sato R. Sone H. Osuga J.I. Ishibashi S. Yamada N. Mol. Endocrinol. 2003; 7: 1240-1254Crossref Scopus (216) Google Scholar, 16Ide T. Shimano H. Yoshikawa T. Yahagi N. Amemiya-Kudo M. Matsuzaka T. Nakakuki M. Yatoh S. Iizuka Y. Tomita S. Ohashi K. Takahashi A. Sone H. Gotoda T. Osuga J.I. Ishibashi S. Yamada N. Mol. Endocrinol. 2003; 7: 1255-1267Crossref Scopus (148) Google Scholar). Our that the protein interaction between HNF-4α and SREBP-1c HNF-4α that transcription factors involved in glucose and are highly related in mutual and for cross-talk in a of nutritional transcription Although the role of PGC-1 in HNF-4α regulation of gluconeogenic genes has been the mechanism for HNF-4α in HNF-4α target genes is not of SREBP effects on HNF-4α could be SREBP of HNF-4α in gluconeogenesis. In fact, SREBP overexpression did not hepatic expression of genes that have been shown to be HNF-4α in HNF-4α knockout mice G. Gonzalez F.J. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). and in the of SREBP interaction SREBP transactivation of sterol regulatory genes in K. T. N. Y. Inoue J. N. Shimano H. M. Sato R. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The of interaction could target genes, and Insulin is the potent negative regulator of PEPCK gene SREBP-1c has been to be induced as of insulin/glucose effects in the liver A.H. Shimano H. Yahagi N. Amemiya-Kudo M. S. Yoshikawa T. Osuga J. Okazaki H. Tamura Y. Iizuka Y. F. Ohashi K. K. Gotoda T. R. Ishibashi S. Yamada N. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, I. Y. S. Horton J.D. Brown M.S. Goldstein J.L. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google Scholar). it is to that insulin of PEPCK expression could be at through SREBP of PEPCK this of the mechanism for nutritional induction of The HNF-4α and SREBP-1c interaction in hepatic glucose be in to the of hepatic insulin and Considering a role of HNF-4α as a gene for of K. H. N. S. S. M. Nature. 1996; PubMed Scopus Google Scholar, H. N. N. Y. Y. K. N. J. M. H. Y. Y. 1997; PubMed Scopus Google Scholar, L. P. J.C. E. A. F. N. H. G. B. P. J. Clin. Investig. PubMed Scopus Google Scholar), it also be to investigate roles of SREBP and HNF-4α in in of insulin and The a novel role of SREBP in the transcriptional regulation of gluconeogenesis and that the SREBP-1 not as a regulator also as a regulator of glucose the transcriptional regulation of gluconeogenesis. A. H. Hasty for of the also T. for and
Yamamoto et al. (Mon,) studied this question.