SemOpenAlex |

SemOpenAlex

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2172132693> ?p ?o ?g. }

Showing items 1 to 100 of ±146 with 100 items per page.

W2172132693 endingPage "1592" @default.
W2172132693 startingPage "1586" @default.
W2172132693 abstract "Small heterodimer partner (SHP, NR0B2) is an atypical orphan nuclear receptor that inhibits transcriptional activation by several other nuclear receptors. We recently reported that mutations in the SHP gene are associated with insulin resistance. In the present study, we demonstrated that theSHP gene is expressed in adipose tissues. A reporter gene assay showed that a gene product of SHP increased the transcriptional activation of peroxisome proliferator-activated receptor (PPAR) γ. SHP-mediated activation of PPARγ was observed both in the presence and absence of the ligand of PPARγ. Immunoprecipitation and glutathione S-transferase pull-down assay showed that SHP directly bound to PPARγ and competed with nuclear receptor corepressor for binding to PPARγ. Serial deletion studies indicated that the C terminus of SHP is important for PPARγ activation. Mutant SHP proteins, which are found in naturally occurring mutation, showed less enhancing activity for PPARγ than wild-type SHP. Our results suggest that SHP may act as an endogenous enhancer of PPARγ. Small heterodimer partner (SHP, NR0B2) is an atypical orphan nuclear receptor that inhibits transcriptional activation by several other nuclear receptors. We recently reported that mutations in the SHP gene are associated with insulin resistance. In the present study, we demonstrated that theSHP gene is expressed in adipose tissues. A reporter gene assay showed that a gene product of SHP increased the transcriptional activation of peroxisome proliferator-activated receptor (PPAR) γ. SHP-mediated activation of PPARγ was observed both in the presence and absence of the ligand of PPARγ. Immunoprecipitation and glutathione S-transferase pull-down assay showed that SHP directly bound to PPARγ and competed with nuclear receptor corepressor for binding to PPARγ. Serial deletion studies indicated that the C terminus of SHP is important for PPARγ activation. Mutant SHP proteins, which are found in naturally occurring mutation, showed less enhancing activity for PPARγ than wild-type SHP. Our results suggest that SHP may act as an endogenous enhancer of PPARγ. ligand-independent transactivation domain ligand-dependent transactivation domain small heterodimer partner peroxisome proliferator-activated receptor nuclear receptor corepressor DNA-binding domain reverse transcription retinoid X receptor hepatocyte nuclear factor estrogen receptor thyroid hormone receptor retinoic acid receptor PPAR response element thymidine kinase estrogen response element Dulbecco's modified Eagle's medium fetal calf serum hemagglutinin glutathione S-transferase troglitazone pioglitazone rosiglitazone retinoic acid wild-type PPARγ coactivator-1 liver receptor homolog-1 steroid receptor coactivator-1 The nuclear receptor superfamily is a group of transcription factors that regulate target genes in response to small lipophilic compounds such as steroids, thyroid hormone, and retinoids (1Beato M. Herrlich P. Schutz G. Cell. 1995; 83: 851-857Google Scholar, 2Mangelsdorf D.J. Evans R.M. Cell. 1995; 83: 841-850Google Scholar, 3Enmark E. Gustafsson J.A. Mol. Endocrinol. 1996; 10: 1293-1307Google Scholar, 4Owen G.I. Zelent A. Cell. Mol. Life Sci. 2000; 57: 809-827Google Scholar). In general, these nuclear receptors consist of several functional domains: an N-terminal ligand-independent transactivation domain (AF-11), a DNA-binding domain (DBD) that contains two zinc fingers, a hinge domain that is a variable linker region and a functionally complex C-terminal region that includes the ligand-binding domain, the dimerization interface, and the ligand-dependent transactivation domain (AF-2) (1Beato M. Herrlich P. Schutz G. Cell. 1995; 83: 851-857Google Scholar, 2Mangelsdorf D.J. Evans R.M. Cell. 1995; 83: 841-850Google Scholar, 3Enmark E. Gustafsson J.A. Mol. Endocrinol. 1996; 10: 1293-1307Google Scholar, 4Owen G.I. Zelent A. Cell. Mol. Life Sci. 2000; 57: 809-827Google Scholar). These nuclear receptors regulate expression of genes that function in a variety of metabolic pathways.Peroxisome proliferator-activated receptor (PPAR) γ is a transcription factor, belonging to the nuclear receptor superfamily. PPARγ is a master regulator for adipocyte differentiation (5Tontonoz P. Hu E. Graves R.A. Budavari A.I. Spiegelman B.M. Genes Dev. 1994; 8: 1224-1234Google Scholar, 6Tontonoz P. Hu E. Spiegelman B.M. Cell. 1994; 79: 1147-1156Google Scholar) and is important in regulation of a number of genes involved in fatty acid and glucose metabolism (7Lefebvre A.M. Peinado-Onsurbe J. Leitersdorf I. Briggs M.R. Paterniti J.R. Fruchart J.C. Fievet C. Auwerx J. Staels B. Arterioscler. Thromb. Vasc. Biol. 1997; 17: 1756-1764Google Scholar, 8Young P.W. Cawthorne M.A. Coyle P.J. Holder J.C. Holman G.D. Kozka I.J. Kirkham D.M. Lister C.A. Smith S.A. Diabetes. 1995; 44: 1087-1092Google Scholar, 9Wu Z. Xie Y. Morrison R.F. Bucher N.L. Farmer S.R. J. Clin. Invest. 1998; 101: 22-32Google Scholar). Synthetic PPARγ ligands, thiazolidinedione drugs, increase insulin sensitivity and are used in the treatment of diabetic patients (10Iwamoto Y. Kuzuya T. Matsuda A. Awata T. Kumakura S. Inooka G. Shiraishi I. Diabetes Care. 1991; 14: 1083-1086Google Scholar, 11Fujiwara T. Yoshioka S. Yoshioka T. Ushiyama I. Horikoshi H. Diabetes. 1988; 37: 1549-1558Google Scholar, 12Day C. Diabet. Med. 1999; 16: 179-192Google Scholar). In contrast, individuals with a loss-of-function mutation in the PPARγ gene developed early-onset type 2 diabetes with severe insulin resistance (13Barroso I. Gurnell M. Crowley V.E. Agostini M. Schwabe J.W. Soos M.A. Maslen G.L. Williams T.D. Lewis H. Schafer A.J. Chatterjee V.K. O'Rahilly S. Nature. 1999; 402: 880-883Google Scholar). Therefore, endogenous modulators of PPARγ should affect the insulin sensitivity.Small heterodimer partner (SHP, NR0B2) is an atypical orphan nuclear receptor composed of 257 amino acids (human protein) or 260 amino acids (murine protein) that lacks a conventional DBD (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar). It has been reported that SHP interacts with several other nuclear receptors and modulates the transcriptional activities (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar, 15Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Google Scholar, 16Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Google Scholar, 17Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Google Scholar, 18Goodwin B. Jones S.A. Price R.R. Watson M.A. McKee D.D. Moore L.B. Galardi C. Wilson J.G. Lewis M.C. Roth M.E. Maloney P.R. Willson T.M. Kliewer S.A. Mol. Cell. 2000; 6: 517-526Google Scholar, 19Nishigori H. Tomura H. Tonooka N. Kanamori M. Yamada S. Sho K. Inoue I. Kikuchi N. Onigata K. Kojima I. Kohama T. Yamagata K. Yang Q. Matsuzawa Y. Miki T. Seino S. Kim M.Y. Choi H.S. Lee Y.K. Moore D.D. Takeda J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 575-580Google Scholar). Recently we reported that mutations in SHP gene in humans associated with insulin resistance and mild obesity (19Nishigori H. Tomura H. Tonooka N. Kanamori M. Yamada S. Sho K. Inoue I. Kikuchi N. Onigata K. Kojima I. Kohama T. Yamagata K. Yang Q. Matsuzawa Y. Miki T. Seino S. Kim M.Y. Choi H.S. Lee Y.K. Moore D.D. Takeda J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 575-580Google Scholar). The underlying mechanism by which mutations in SHP gene represented such phenotypes has been unclear. We hypothesized that SHP might affect the transcriptional activation activity of PPARγ.In the present study, we demonstrated that SHP up-regulated the transcriptional activity of PPARγ through the direct binding to the DBD/hinge region of PPARγ. SHP inhibited the repressor activity of nuclear receptor corepressor (NCoR). The mutant SHP proteins found in the subjects with SHP mutation had decreased activation activity for PPARγ. Our data suggest that SHP may act as an endogenous enhancer of PPARγ.DISCUSSIONSHP was originally cloned, by a yeast two-hybrid system, as an associate protein to mCAR, a close murine relative of the human orphan nuclear receptor MB67 (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar, 30Baes M. Gulick T. Choi H.S. Martinoli M.G. Simha D. Moore D.D. Mol. Cell. Biol. 1994; 14: 1544-1551Google Scholar). To date, SHP has been reported to function as a repressor of various nuclear receptors, including RAR, TR, RXR, ER, HNF4α and LRH-1 (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar, 15Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Google Scholar, 16Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Google Scholar, 17Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Google Scholar, 18Goodwin B. Jones S.A. Price R.R. Watson M.A. McKee D.D. Moore L.B. Galardi C. Wilson J.G. Lewis M.C. Roth M.E. Maloney P.R. Willson T.M. Kliewer S.A. Mol. Cell. 2000; 6: 517-526Google Scholar, 19Nishigori H. Tomura H. Tonooka N. Kanamori M. Yamada S. Sho K. Inoue I. Kikuchi N. Onigata K. Kojima I. Kohama T. Yamagata K. Yang Q. Matsuzawa Y. Miki T. Seino S. Kim M.Y. Choi H.S. Lee Y.K. Moore D.D. Takeda J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 575-580Google Scholar). SHP mRNA is expressed abundantly in the liver, heart, and pancreas (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar), but its transcript has been detected quite ubiquitously (15Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Google Scholar). The effect of SHP on transactivation activity of PPARγ has not been evaluated. In the present study, we demonstrated that SHP mRNA is expressed in adipose tissues, in which PPARγ predominantly functions. Unlike other nuclear receptors, SHP increased the transcriptional activity of PPARγ. This activation was significantly diminished in the mutant SHP proteins found in naturally occurring mutations.The interaction of SHP with PPARγ was quite different from that with other nuclear receptors. In previous studies, SHP exhibited repressor activity in its C terminus and functioned by binding to the AF-2 domain of the target receptors (15Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Google Scholar, 16Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Google Scholar, 17Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Google Scholar). In contrast, we demonstrated that SHP bound to a part of the DBD and the hinge domain of PPARγ and exerted enhancing activity at the C terminus. However, the precise molecular mechanism by which SHP activates the transcriptional activity of the PPARγ·RXRα heterodimer is not clear, however, one or more of the following mechanisms might be involved: 1) SHP might directly inhibit the binding of the PPARγ·RXRα complex to PPRE (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar). 2) SHP might compete with the corepressors for binding to PPARγ. 3) SHP may possess its own activating function in its C terminus (17Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Google Scholar). SHP inhibited DNA binding of RAR·RXR (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar) but showed no effect on that of ERα, HNF4α, or LRH-1 (15Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Google Scholar, 16Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Google Scholar, 18Goodwin B. Jones S.A. Price R.R. Watson M.A. McKee D.D. Moore L.B. Galardi C. Wilson J.G. Lewis M.C. Roth M.E. Maloney P.R. Willson T.M. Kliewer S.A. Mol. Cell. 2000; 6: 517-526Google Scholar). In the present study, we were unable to demonstrate a significant effect of SHP on binding of PPARγ·RXRα to PPRE (data not shown). SHP competes with some coactivators for binding to nuclear receptors, including SRC-3 to HNF4α and TIF2 to ERα (15Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Google Scholar, 16Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Google Scholar). NCoR functions as a corepressor for PPARγ. In our study, SHP competed with NCoR for binding to PPARγ and increased the activity. Dissociation of NCoR may cause a conformational change of PPARγ with subsequent activation. Other mechanisms may be involved in this augmentation, because SHP still enhanced PPARγ activity even in the presence of its ligand, in which NCoR dissociates from PPARγ (27Oberfield J.L. Collins J.L. Holmes C.P. Goreham D.M. Cooper J.P. Cobb J.E. Lenhard J.M. Hull-Ryde E.A. Mohr C.P. Blanchard S.G. Parks D.J. Moore L.B. Lehmann J.M. Plunket K. Miller A.B. Milburn M.V. Kliewer S.A. Willson T.M. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 6102-6106Google Scholar). PGC-1 is one of the coactivators of PPARγ (26Puigserver P. Wu Z. Park C.W. Graves R. Wright M. Spiegelman B.M. Cell. 1998; 92: 829-839Google Scholar). Docking of PGC-1 to the DBD/hinge domain of PPARγ results in a state permissive for binding of other cofactors such as SRC-1 and CREB-binding protein, followed by activation of the receptor (31Puigserver P. Adelmant G. Wu Z. Fan M. Xu J. O'Malley B. Spiegelman B.M. Science. 1999; 286: 1368-1371Google Scholar). SHP may activate PPARγ by a mechanism similar to PGC-1.Our results also showed that mutant SHP proteins, found in naturally occurring mutations, had less enhancing activity for PPARγ than WT-SHP. All mutants have an abnormal C-terminal region. Serial C-terminal deletion mutants also showed less enhancing activity. These mutant proteins had a normal N terminus and retained the binding activity for PPARγ. In this regard, a recent report (32Johansson L. Bavner A. Thomsen J.S. Farnegardh M. Gustafsson J.A. Treuter E. Mol. Cell. Biol. 2000; 20: 1124-1133Google Scholar) has demonstrated that the LXXLL-related motif in the N terminus of SHP is important for binding to ER. Another atypical orphan receptor, DAX-1, which is the closest relative of SHP, also has a binding domain for nuclear receptors in the N terminus (33Ito M. Yu R. Jameson J.L. Mol. Cell. Biol. 1997; 17: 1476-1483Google Scholar, 34Zazopoulos E. Lalli E. Stocco D.M. Sassone-Corsi P. Nature. 1997; 390: 311-315Google Scholar, 35Zanaria E. Muscatelli F. Bardoni B. Strom T.M. Guioli S. Guo W. Lalli E. Moser C. Walker A.P. McCabe E.R. Meitinger T. Monaco A.P. Sassone-Corsi P. Camerio G. Nature. 1994; 372: 635-6341Google Scholar). The C terminus of SHP may activate PPARγ in co-operation with the N-terminal domain. Accordingly, further investigation of the functional interaction between the N- and C-terminal regions should provide new insight into the mechanism(s) of SHP-mediated PPARγ transactivation. It has been reported that SHP represses the activity of the RXR homodimer to the RXRE-containing promoter (16Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Google Scholar). Although SHP increases the activity of PPARγ·RXRα heterodimer complex, it is possible that the mutant SHP proteins with the abnormal C terminus may have a more potent repressor activity for RXRα than WT, resulting in reduced activity for the PPARγ·RXRα complex. Further studies are necessary to analyze the direct effect of SHP on the heterodimeric partner RXRα of the PPARγ complex.Genetic mutations of SHP in human subjects are associated with insulin resistance and mild obesity (19Nishigori H. Tomura H. Tonooka N. Kanamori M. Yamada S. Sho K. Inoue I. Kikuchi N. Onigata K. Kojima I. Kohama T. Yamagata K. Yang Q. Matsuzawa Y. Miki T. Seino S. Kim M.Y. Choi H.S. Lee Y.K. Moore D.D. Takeda J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 575-580Google Scholar). Activation of PPARγ by its synthetic ligands increases insulin sensitivity (10Iwamoto Y. Kuzuya T. Matsuda A. Awata T. Kumakura S. Inooka G. Shiraishi I. Diabetes Care. 1991; 14: 1083-1086Google Scholar, 11Fujiwara T. Yoshioka S. Yoshioka T. Ushiyama I. Horikoshi H. Diabetes. 1988; 37: 1549-1558Google Scholar, 12Day C. Diabet. Med. 1999; 16: 179-192Google Scholar). Individuals with a dominant negative mutation of the PPARγ gene have been reported to develop severe insulin resistance (13Barroso I. Gurnell M. Crowley V.E. Agostini M. Schwabe J.W. Soos M.A. Maslen G.L. Williams T.D. Lewis H. Schafer A.J. Chatterjee V.K. O'Rahilly S. Nature. 1999; 402: 880-883Google Scholar). In the present study, we showed that mutant SHPs exhibit less enhancing activity on PPARγ than WT. These observations suggest that less enhancing activity of PPARγ by mutant SHP proteins may be involved in insulin resistance in subjects with SHP mutation. On the other hand, it is still not clear how SHP mutations contribute to mild obesity. SHP mutations are associated with abnormally high birth weight and early-onset obesity (19Nishigori H. Tomura H. Tonooka N. Kanamori M. Yamada S. Sho K. Inoue I. Kikuchi N. Onigata K. Kojima I. Kohama T. Yamagata K. Yang Q. Matsuzawa Y. Miki T. Seino S. Kim M.Y. Choi H.S. Lee Y.K. Moore D.D. Takeda J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 575-580Google Scholar). Because SHP inhibits the activities of various other nuclear receptors, including RAR, TR, ER, HNF4α, and LRH-1, the clinical phenotypes of the SHP mutation cannot be accounted for only by the SHP-PPARγ pathway. Loss of SHP function might lead to increased activity of HNF4α and may increase the secretion of insulin from pancreatic β-cells. Because insulin is one of the key hormones involved in adipogenesis, increased insulin secretion in utero could promote intrauterine growth of adipose tissue and predispose to postnatal obesity in affected individuals.Although detailed analysis of SHP interaction with PPARγ remains to be completed, our finding that SHP enhances the transcriptional activity of PPARγ might allow the design of new approaches to the treatment of insulin resistance syndrome. Because SHP has a putative ligand-binding domain in the C-terminal region, identification of the putative SHP ligands or agonists may allow the design of a new class of therapeutic agents to combat insulin resistance. The nuclear receptor superfamily is a group of transcription factors that regulate target genes in response to small lipophilic compounds such as steroids, thyroid hormone, and retinoids (1Beato M. Herrlich P. Schutz G. Cell. 1995; 83: 851-857Google Scholar, 2Mangelsdorf D.J. Evans R.M. Cell. 1995; 83: 841-850Google Scholar, 3Enmark E. Gustafsson J.A. Mol. Endocrinol. 1996; 10: 1293-1307Google Scholar, 4Owen G.I. Zelent A. Cell. Mol. Life Sci. 2000; 57: 809-827Google Scholar). In general, these nuclear receptors consist of several functional domains: an N-terminal ligand-independent transactivation domain (AF-11), a DNA-binding domain (DBD) that contains two zinc fingers, a hinge domain that is a variable linker region and a functionally complex C-terminal region that includes the ligand-binding domain, the dimerization interface, and the ligand-dependent transactivation domain (AF-2) (1Beato M. Herrlich P. Schutz G. Cell. 1995; 83: 851-857Google Scholar, 2Mangelsdorf D.J. Evans R.M. Cell. 1995; 83: 841-850Google Scholar, 3Enmark E. Gustafsson J.A. Mol. Endocrinol. 1996; 10: 1293-1307Google Scholar, 4Owen G.I. Zelent A. Cell. Mol. Life Sci. 2000; 57: 809-827Google Scholar). These nuclear receptors regulate expression of genes that function in a variety of metabolic pathways. Peroxisome proliferator-activated receptor (PPAR) γ is a transcription factor, belonging to the nuclear receptor superfamily. PPARγ is a master regulator for adipocyte differentiation (5Tontonoz P. Hu E. Graves R.A. Budavari A.I. Spiegelman B.M. Genes Dev. 1994; 8: 1224-1234Google Scholar, 6Tontonoz P. Hu E. Spiegelman B.M. Cell. 1994; 79: 1147-1156Google Scholar) and is important in regulation of a number of genes involved in fatty acid and glucose metabolism (7Lefebvre A.M. Peinado-Onsurbe J. Leitersdorf I. Briggs M.R. Paterniti J.R. Fruchart J.C. Fievet C. Auwerx J. Staels B. Arterioscler. Thromb. Vasc. Biol. 1997; 17: 1756-1764Google Scholar, 8Young P.W. Cawthorne M.A. Coyle P.J. Holder J.C. Holman G.D. Kozka I.J. Kirkham D.M. Lister C.A. Smith S.A. Diabetes. 1995; 44: 1087-1092Google Scholar, 9Wu Z. Xie Y. Morrison R.F. Bucher N.L. Farmer S.R. J. Clin. Invest. 1998; 101: 22-32Google Scholar). Synthetic PPARγ ligands, thiazolidinedione drugs, increase insulin sensitivity and are used in the treatment of diabetic patients (10Iwamoto Y. Kuzuya T. Matsuda A. Awata T. Kumakura S. Inooka G. Shiraishi I. Diabetes Care. 1991; 14: 1083-1086Google Scholar, 11Fujiwara T. Yoshioka S. Yoshioka T. Ushiyama I. Horikoshi H. Diabetes. 1988; 37: 1549-1558Google Scholar, 12Day C. Diabet. Med. 1999; 16: 179-192Google Scholar). In contrast, individuals with a loss-of-function mutation in the PPARγ gene developed early-onset type 2 diabetes with severe insulin resistance (13Barroso I. Gurnell M. Crowley V.E. Agostini M. Schwabe J.W. Soos M.A. Maslen G.L. Williams T.D. Lewis H. Schafer A.J. Chatterjee V.K. O'Rahilly S. Nature. 1999; 402: 880-883Google Scholar). Therefore, endogenous modulators of PPARγ should affect the insulin sensitivity. Small heterodimer partner (SHP, NR0B2) is an atypical orphan nuclear receptor composed of 257 amino acids (human protein) or 260 amino acids (murine protein) that lacks a conventional DBD (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar). It has been reported that SHP interacts with several other nuclear receptors and modulates the transcriptional activities (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar, 15Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Google Scholar, 16Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Google Scholar, 17Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Google Scholar, 18Goodwin B. Jones S.A. Price R.R. Watson M.A. McKee D.D. Moore L.B. Galardi C. Wilson J.G. Lewis M.C. Roth M.E. Maloney P.R. Willson T.M. Kliewer S.A. Mol. Cell. 2000; 6: 517-526Google Scholar, 19Nishigori H. Tomura H. Tonooka N. Kanamori M. Yamada S. Sho K. Inoue I. Kikuchi N. Onigata K. Kojima I. Kohama T. Yamagata K. Yang Q. Matsuzawa Y. Miki T. Seino S. Kim M.Y. Choi H.S. Lee Y.K. Moore D.D. Takeda J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 575-580Google Scholar). Recently we reported that mutations in SHP gene in humans associated with insulin resistance and mild obesity (19Nishigori H. Tomura H. Tonooka N. Kanamori M. Yamada S. Sho K. Inoue I. Kikuchi N. Onigata K. Kojima I. Kohama T. Yamagata K. Yang Q. Matsuzawa Y. Miki T. Seino S. Kim M.Y. Choi H.S. Lee Y.K. Moore D.D. Takeda J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 575-580Google Scholar). The underlying mechanism by which mutations in SHP gene represented such phenotypes has been unclear. We hypothesized that SHP might affect the transcriptional activation activity of PPARγ. In the present study, we demonstrated that SHP up-regulated the transcriptional activity of PPARγ through the direct binding to the DBD/hinge region of PPARγ. SHP inhibited the repressor activity of nuclear receptor corepressor (NCoR). The mutant SHP proteins found in the subjects with SHP mutation had decreased activation activity for PPARγ. Our data suggest that SHP may act as an endogenous enhancer of PPARγ. DISCUSSIONSHP was originally cloned, by a yeast two-hybrid system, as an associate protein to mCAR, a close murine relative of the human orphan nuclear receptor MB67 (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar, 30Baes M. Gulick T. Choi H.S. Martinoli M.G. Simha D. Moore D.D. Mol. Cell. Biol. 1994; 14: 1544-1551Google Scholar). To date, SHP has been reported to function as a repressor of various nuclear receptors, including RAR, TR, RXR, ER, HNF4α and LRH-1 (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar, 15Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Google Scholar, 16Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Google Scholar, 17Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Google Scholar, 18Goodwin B. Jones S.A. Price R.R. Watson M.A. McKee D.D. Moore L.B. Galardi C. Wilson J.G. Lewis M.C. Roth M.E. Maloney P.R. Willson T.M. Kliewer S.A. Mol. Cell. 2000; 6: 517-526Google Scholar, 19Nishigori H. Tomura H. Tonooka N. Kanamori M. Yamada S. Sho K. Inoue I. Kikuchi N. Onigata K. Kojima I. Kohama T. Yamagata K. Yang Q. Matsuzawa Y. Miki T. Seino S. Kim M.Y. Choi H.S. Lee Y.K. Moore D.D. Takeda J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 575-580Google Scholar). SHP mRNA is expressed abundantly in the liver, heart, and pancreas (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar), but its transcript has been detected quite ubiquitously (15Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Google Scholar). The effect of SHP on transactivation activity of PPARγ has not been evaluated. In the present study, we demonstrated that SHP mRNA is expressed in adipose tissues, in which PPARγ predominantly functions. Unlike other nuclear receptors, SHP increased the transcriptional activity of PPARγ. This activation was significantly diminished in the mutant SHP proteins found in naturally occurring mutations.The interaction of SHP with PPARγ was quite different from that with other nuclear receptors. In previous studies, SHP exhibited repressor activity in its C terminus and functioned by binding to the AF-2 domain of the target receptors (15Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Google Scholar, 16Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Google Scholar, 17Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Google Scholar). In contrast, we demonstrated that SHP bound to a part of the DBD and the hinge domain of PPARγ and exerted enhancing activity at the C terminus. However, the precise molecular mechanism by which SHP activates the transcriptional activity of the PPARγ·RXRα heterodimer is not clear, however, one or more of the following mechanisms might be involved: 1) SHP might directly inhibit the binding of the PPARγ·RXRα complex to PPRE (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar). 2) SHP might compete with the corepressors for binding to PPARγ. 3) SHP may possess its own activating function in its C terminus (17Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Google Scholar). SHP inhibited DNA binding of RAR·RXR (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar) but showed no effect on that of ERα, HNF4α, or LRH-1 (15Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Google Scholar, 16Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Google Scholar, 18Goodwin B. Jones S.A. Price R.R. Watson M.A. McKee D.D. Moore L.B. Galardi C. Wilson J.G. Lewis M.C. Roth M.E. Maloney P.R. Willson T.M. Kliewer S.A. Mol. Cell. 2000; 6: 517-526Google Scholar). In the present study, we were unable to demonstrate a significant effect of SHP on binding of PPARγ·RXRα to PPRE (data not shown). SHP competes with some coactivators for binding to nuclear receptors, including SRC-3 to HNF4α and TIF2 to ERα (15Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Google Scholar, 16Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Google Scholar). NCoR functions as a corepressor for PPARγ. In our study, SHP competed with NCoR for binding to PPARγ and increased the activity. Dissociation of NCoR may cause a conformational change of PPARγ with subsequent activation. Other mechanisms may be involved in this augmentation, because SHP still enhanced PPARγ activity even in the presence of its ligand, in which NCoR dissociates from PPARγ (27Oberfield J.L. Collins J.L. Holmes C.P. Goreham D.M. Cooper J.P. Cobb J.E. Lenhard J.M. Hull-Ryde E.A. Mohr C.P. Blanchard S.G. Parks D.J. Moore L.B. Lehmann J.M. Plunket K. Miller A.B. Milburn M.V. Kliewer S.A. Willson T.M. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 6102-6106Google Scholar). PGC-1 is one of the coactivators of PPARγ (26Puigserver P. Wu Z. Park C.W. Graves R. Wright M. Spiegelman B.M. Cell. 1998; 92: 829-839Google Scholar). Docking of PGC-1 to the DBD/hinge domain of PPARγ results in a state permissive for binding of other cofactors such as SRC-1 and CREB-binding protein, followed by activation of the receptor (31Puigserver P. Adelmant G. Wu Z. Fan M. Xu J. O'Malley B. Spiegelman B.M. Science. 1999; 286: 1368-1371Google Scholar). SHP may activate PPARγ by a mechanism similar to PGC-1.Our results also showed that mutant SHP proteins, found in naturally occurring mutations, had less enhancing activity for PPARγ than WT-SHP. All mutants have an abnormal C-terminal region. Serial C-terminal deletion mutants also showed less enhancing activity. These mutant proteins had a normal N terminus and retained the binding activity for PPARγ. In this regard, a recent report (32Johansson L. Bavner A. Thomsen J.S. Farnegardh M. Gustafsson J.A. Treuter E. Mol. Cell. Biol. 2000; 20: 1124-1133Google Scholar) has demonstrated that the LXXLL-related motif in the N terminus of SHP is important for binding to ER. Another atypical orphan receptor, DAX-1, which is the closest relative of SHP, also has a binding domain for nuclear receptors in the N terminus (33Ito M. Yu R. Jameson J.L. Mol. Cell. Biol. 1997; 17: 1476-1483Google Scholar, 34Zazopoulos E. Lalli E. Stocco D.M. Sassone-Corsi P. Nature. 1997; 390: 311-315Google Scholar, 35Zanaria E. Muscatelli F. Bardoni B. Strom T.M. Guioli S. Guo W. Lalli E. Moser C. Walker A.P. McCabe E.R. Meitinger T. Monaco A.P. Sassone-Corsi P. Camerio G. Nature. 1994; 372: 635-6341Google Scholar). The C terminus of SHP may activate PPARγ in co-operation with the N-terminal domain. Accordingly, further investigation of the functional interaction between the N- and C-terminal regions should provide new insight into the mechanism(s) of SHP-mediated PPARγ transactivation. It has been reported that SHP represses the activity of the RXR homodimer to the RXRE-containing promoter (16Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Google Scholar). Although SHP increases the activity of PPARγ·RXRα heterodimer complex, it is possible that the mutant SHP proteins with the abnormal C terminus may have a more potent repressor activity for RXRα than WT, resulting in reduced activity for the PPARγ·RXRα complex. Further studies are necessary to analyze the direct effect of SHP on the heterodimeric partner RXRα of the PPARγ complex.Genetic mutations of SHP in human subjects are associated with insulin resistance and mild obesity (19Nishigori H. Tomura H. Tonooka N. Kanamori M. Yamada S. Sho K. Inoue I. Kikuchi N. Onigata K. Kojima I. Kohama T. Yamagata K. Yang Q. Matsuzawa Y. Miki T. Seino S. Kim M.Y. Choi H.S. Lee Y.K. Moore D.D. Takeda J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 575-580Google Scholar). Activation of PPARγ by its synthetic ligands increases insulin sensitivity (10Iwamoto Y. Kuzuya T. Matsuda A. Awata T. Kumakura S. Inooka G. Shiraishi I. Diabetes Care. 1991; 14: 1083-1086Google Scholar, 11Fujiwara T. Yoshioka S. Yoshioka T. Ushiyama I. Horikoshi H. Diabetes. 1988; 37: 1549-1558Google Scholar, 12Day C. Diabet. Med. 1999; 16: 179-192Google Scholar). Individuals with a dominant negative mutation of the PPARγ gene have been reported to develop severe insulin resistance (13Barroso I. Gurnell M. Crowley V.E. Agostini M. Schwabe J.W. Soos M.A. Maslen G.L. Williams T.D. Lewis H. Schafer A.J. Chatterjee V.K. O'Rahilly S. Nature. 1999; 402: 880-883Google Scholar). In the present study, we showed that mutant SHPs exhibit less enhancing activity on PPARγ than WT. These observations suggest that less enhancing activity of PPARγ by mutant SHP proteins may be involved in insulin resistance in subjects with SHP mutation. On the other hand, it is still not clear how SHP mutations contribute to mild obesity. SHP mutations are associated with abnormally high birth weight and early-onset obesity (19Nishigori H. Tomura H. Tonooka N. Kanamori M. Yamada S. Sho K. Inoue I. Kikuchi N. Onigata K. Kojima I. Kohama T. Yamagata K. Yang Q. Matsuzawa Y. Miki T. Seino S. Kim M.Y. Choi H.S. Lee Y.K. Moore D.D. Takeda J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 575-580Google Scholar). Because SHP inhibits the activities of various other nuclear receptors, including RAR, TR, ER, HNF4α, and LRH-1, the clinical phenotypes of the SHP mutation cannot be accounted for only by the SHP-PPARγ pathway. Loss of SHP function might lead to increased activity of HNF4α and may increase the secretion of insulin from pancreatic β-cells. Because insulin is one of the key hormones involved in adipogenesis, increased insulin secretion in utero could promote intrauterine growth of adipose tissue and predispose to postnatal obesity in affected individuals.Although detailed analysis of SHP interaction with PPARγ remains to be completed, our finding that SHP enhances the transcriptional activity of PPARγ might allow the design of new approaches to the treatment of insulin resistance syndrome. Because SHP has a putative ligand-binding domain in the C-terminal region, identification of the putative SHP ligands or agonists may allow the design of a new class of therapeutic agents to combat insulin resistance. SHP was originally cloned, by a yeast two-hybrid system, as an associate protein to mCAR, a close murine relative of the human orphan nuclear receptor MB67 (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar, 30Baes M. Gulick T. Choi H.S. Martinoli M.G. Simha D. Moore D.D. Mol. Cell. Biol. 1994; 14: 1544-1551Google Scholar). To date, SHP has been reported to function as a repressor of various nuclear receptors, including RAR, TR, RXR, ER, HNF4α and LRH-1 (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar, 15Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Google Scholar, 16Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Google Scholar, 17Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Google Scholar, 18Goodwin B. Jones S.A. Price R.R. Watson M.A. McKee D.D. Moore L.B. Galardi C. Wilson J.G. Lewis M.C. Roth M.E. Maloney P.R. Willson T.M. Kliewer S.A. Mol. Cell. 2000; 6: 517-526Google Scholar, 19Nishigori H. Tomura H. Tonooka N. Kanamori M. Yamada S. Sho K. Inoue I. Kikuchi N. Onigata K. Kojima I. Kohama T. Yamagata K. Yang Q. Matsuzawa Y. Miki T. Seino S. Kim M.Y. Choi H.S. Lee Y.K. Moore D.D. Takeda J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 575-580Google Scholar). SHP mRNA is expressed abundantly in the liver, heart, and pancreas (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar), but its transcript has been detected quite ubiquitously (15Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Google Scholar). The effect of SHP on transactivation activity of PPARγ has not been evaluated. In the present study, we demonstrated that SHP mRNA is expressed in adipose tissues, in which PPARγ predominantly functions. Unlike other nuclear receptors, SHP increased the transcriptional activity of PPARγ. This activation was significantly diminished in the mutant SHP proteins found in naturally occurring mutations. The interaction of SHP with PPARγ was quite different from that with other nuclear receptors. In previous studies, SHP exhibited repressor activity in its C terminus and functioned by binding to the AF-2 domain of the target receptors (15Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Google Scholar, 16Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Google Scholar, 17Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Google Scholar). In contrast, we demonstrated that SHP bound to a part of the DBD and the hinge domain of PPARγ and exerted enhancing activity at the C terminus. However, the precise molecular mechanism by which SHP activates the transcriptional activity of the PPARγ·RXRα heterodimer is not clear, however, one or more of the following mechanisms might be involved: 1) SHP might directly inhibit the binding of the PPARγ·RXRα complex to PPRE (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar). 2) SHP might compete with the corepressors for binding to PPARγ. 3) SHP may possess its own activating function in its C terminus (17Seol W. Chung M. Moore D.D. Mol. Cell. Biol. 1997; 17: 7126-7131Google Scholar). SHP inhibited DNA binding of RAR·RXR (14Seol W. Choi H.S. Moore D.D. Science. 1996; 272: 1336-1339Google Scholar) but showed no effect on that of ERα, HNF4α, or LRH-1 (15Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Google Scholar, 16Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Google Scholar, 18Goodwin B. Jones S.A. Price R.R. Watson M.A. McKee D.D. Moore L.B. Galardi C. Wilson J.G. Lewis M.C. Roth M.E. Maloney P.R. Willson T.M. Kliewer S.A. Mol. Cell. 2000; 6: 517-526Google Scholar). In the present study, we were unable to demonstrate a significant effect of SHP on binding of PPARγ·RXRα to PPRE (data not shown). SHP competes with some coactivators for binding to nuclear receptors, including SRC-3 to HNF4α and TIF2 to ERα (15Johansson L. Thomsen J.S. Damdimopoulos A.E. Spyrou G. Gustafsson J.A. Treuter E. J. Biol. Chem. 1999; 274: 345-353Google Scholar, 16Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Google Scholar). NCoR functions as a corepressor for PPARγ. In our study, SHP competed with NCoR for binding to PPARγ and increased the activity. Dissociation of NCoR may cause a conformational change of PPARγ with subsequent activation. Other mechanisms may be involved in this augmentation, because SHP still enhanced PPARγ activity even in the presence of its ligand, in which NCoR dissociates from PPARγ (27Oberfield J.L. Collins J.L. Holmes C.P. Goreham D.M. Cooper J.P. Cobb J.E. Lenhard J.M. Hull-Ryde E.A. Mohr C.P. Blanchard S.G. Parks D.J. Moore L.B. Lehmann J.M. Plunket K. Miller A.B. Milburn M.V. Kliewer S.A. Willson T.M. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 6102-6106Google Scholar). PGC-1 is one of the coactivators of PPARγ (26Puigserver P. Wu Z. Park C.W. Graves R. Wright M. Spiegelman B.M. Cell. 1998; 92: 829-839Google Scholar). Docking of PGC-1 to the DBD/hinge domain of PPARγ results in a state permissive for binding of other cofactors such as SRC-1 and CREB-binding protein, followed by activation of the receptor (31Puigserver P. Adelmant G. Wu Z. Fan M. Xu J. O'Malley B. Spiegelman B.M. Science. 1999; 286: 1368-1371Google Scholar). SHP may activate PPARγ by a mechanism similar to PGC-1. Our results also showed that mutant SHP proteins, found in naturally occurring mutations, had less enhancing activity for PPARγ than WT-SHP. All mutants have an abnormal C-terminal region. Serial C-terminal deletion mutants also showed less enhancing activity. These mutant proteins had a normal N terminus and retained the binding activity for PPARγ. In this regard, a recent report (32Johansson L. Bavner A. Thomsen J.S. Farnegardh M. Gustafsson J.A. Treuter E. Mol. Cell. Biol. 2000; 20: 1124-1133Google Scholar) has demonstrated that the LXXLL-related motif in the N terminus of SHP is important for binding to ER. Another atypical orphan receptor, DAX-1, which is the closest relative of SHP, also has a binding domain for nuclear receptors in the N terminus (33Ito M. Yu R. Jameson J.L. Mol. Cell. Biol. 1997; 17: 1476-1483Google Scholar, 34Zazopoulos E. Lalli E. Stocco D.M. Sassone-Corsi P. Nature. 1997; 390: 311-315Google Scholar, 35Zanaria E. Muscatelli F. Bardoni B. Strom T.M. Guioli S. Guo W. Lalli E. Moser C. Walker A.P. McCabe E.R. Meitinger T. Monaco A.P. Sassone-Corsi P. Camerio G. Nature. 1994; 372: 635-6341Google Scholar). The C terminus of SHP may activate PPARγ in co-operation with the N-terminal domain. Accordingly, further investigation of the functional interaction between the N- and C-terminal regions should provide new insight into the mechanism(s) of SHP-mediated PPARγ transactivation. It has been reported that SHP represses the activity of the RXR homodimer to the RXRE-containing promoter (16Lee Y.K. Dell H. Dowhan D.H. Hadzopoulou-Cladaras M. Moore D.D. Mol. Cell. Biol. 2000; 20: 187-195Google Scholar). Although SHP increases the activity of PPARγ·RXRα heterodimer complex, it is possible that the mutant SHP proteins with the abnormal C terminus may have a more potent repressor activity for RXRα than WT, resulting in reduced activity for the PPARγ·RXRα complex. Further studies are necessary to analyze the direct effect of SHP on the heterodimeric partner RXRα of the PPARγ complex. Genetic mutations of SHP in human subjects are associated with insulin resistance and mild obesity (19Nishigori H. Tomura H. Tonooka N. Kanamori M. Yamada S. Sho K. Inoue I. Kikuchi N. Onigata K. Kojima I. Kohama T. Yamagata K. Yang Q. Matsuzawa Y. Miki T. Seino S. Kim M.Y. Choi H.S. Lee Y.K. Moore D.D. Takeda J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 575-580Google Scholar). Activation of PPARγ by its synthetic ligands increases insulin sensitivity (10Iwamoto Y. Kuzuya T. Matsuda A. Awata T. Kumakura S. Inooka G. Shiraishi I. Diabetes Care. 1991; 14: 1083-1086Google Scholar, 11Fujiwara T. Yoshioka S. Yoshioka T. Ushiyama I. Horikoshi H. Diabetes. 1988; 37: 1549-1558Google Scholar, 12Day C. Diabet. Med. 1999; 16: 179-192Google Scholar). Individuals with a dominant negative mutation of the PPARγ gene have been reported to develop severe insulin resistance (13Barroso I. Gurnell M. Crowley V.E. Agostini M. Schwabe J.W. Soos M.A. Maslen G.L. Williams T.D. Lewis H. Schafer A.J. Chatterjee V.K. O'Rahilly S. Nature. 1999; 402: 880-883Google Scholar). In the present study, we showed that mutant SHPs exhibit less enhancing activity on PPARγ than WT. These observations suggest that less enhancing activity of PPARγ by mutant SHP proteins may be involved in insulin resistance in subjects with SHP mutation. On the other hand, it is still not clear how SHP mutations contribute to mild obesity. SHP mutations are associated with abnormally high birth weight and early-onset obesity (19Nishigori H. Tomura H. Tonooka N. Kanamori M. Yamada S. Sho K. Inoue I. Kikuchi N. Onigata K. Kojima I. Kohama T. Yamagata K. Yang Q. Matsuzawa Y. Miki T. Seino S. Kim M.Y. Choi H.S. Lee Y.K. Moore D.D. Takeda J. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 575-580Google Scholar). Because SHP inhibits the activities of various other nuclear receptors, including RAR, TR, ER, HNF4α, and LRH-1, the clinical phenotypes of the SHP mutation cannot be accounted for only by the SHP-PPARγ pathway. Loss of SHP function might lead to increased activity of HNF4α and may increase the secretion of insulin from pancreatic β-cells. Because insulin is one of the key hormones involved in adipogenesis, increased insulin secretion in utero could promote intrauterine growth of adipose tissue and predispose to postnatal obesity in affected individuals. Although detailed analysis of SHP interaction with PPARγ remains to be completed, our finding that SHP enhances the transcriptional activity of PPARγ might allow the design of new approaches to the treatment of insulin resistance syndrome. Because SHP has a putative ligand-binding domain in the C-terminal region, identification of the putative SHP ligands or agonists may allow the design of a new class of therapeutic agents to combat insulin resistance. We thank Sachiyo Tanaka and Yuko Matsukawa of our laboratory for their helpful technical assistance. We appreciate Drs. Akira Kakizuka and Yasutomi Kamei for kindly providing PPRE-luciferase reporter and ERα expression plasmids, Dr. Shigeyuki Katoh for NCoR plasmid, Dr. Bruce M. Spiegelman for PGC-1 expression plasmid (PGC-1-pSVSPORT), Dr. David J. Mangelsdolf for mPPARγ expression plasmid, and Sankyo Co., Ltd. and Takeda Chem., Ltd. for troglitazone, and pioglitazone, respectively. We also thank Drs. Atsunori Fukuhara and Yoshimi Takai for their technical advice for immunoprecipitation assays and Dr. Makoto Makishima for helpful suggestions." @default.
W2172132693 created "2016-06-24" @default.
W2172132693 creator A5003630359 @default.
W2172132693 creator A5010145586 @default.
W2172132693 creator A5016617567 @default.
W2172132693 creator A5017407991 @default.
W2172132693 creator A5017450232 @default.
W2172132693 creator A5029861032 @default.
W2172132693 creator A5035702067 @default.
W2172132693 creator A5036241830 @default.
W2172132693 creator A5037246488 @default.
W2172132693 creator A5045416314 @default.
W2172132693 creator A5050708630 @default.
W2172132693 creator A5063952385 @default.
W2172132693 creator A5066393135 @default.
W2172132693 creator A5076422953 @default.
W2172132693 creator A5081550907 @default.
W2172132693 creator A5084885924 @default.
W2172132693 creator A5086129270 @default.
W2172132693 creator A5086674835 @default.
W2172132693 date "2002-01-01" @default.
W2172132693 modified "2023-10-05" @default.
W2172132693 title "Small Heterodimer Partner, an Orphan Nuclear Receptor, Augments Peroxisome Proliferator-activated Receptor γ Transactivation" @default.
W2172132693 cites W1488559297 @default.
W2172132693 cites W1527827101 @default.
W2172132693 cites W1660177314 @default.
W2172132693 cites W1976766119 @default.
W2172132693 cites W1979761686 @default.
W2172132693 cites W1986619463 @default.
W2172132693 cites W1987183940 @default.
W2172132693 cites W1990819179 @default.
W2172132693 cites W1994833377 @default.
W2172132693 cites W1995754186 @default.
W2172132693 cites W2002519246 @default.
W2172132693 cites W2008632158 @default.
W2172132693 cites W2011935366 @default.
W2172132693 cites W2027702484 @default.
W2172132693 cites W2029725115 @default.
W2172132693 cites W2037313086 @default.
W2172132693 cites W2042669405 @default.
W2172132693 cites W2043852388 @default.
W2172132693 cites W2046566365 @default.
W2172132693 cites W2068067085 @default.
W2172132693 cites W2068113812 @default.
W2172132693 cites W2069532898 @default.
W2172132693 cites W2070428103 @default.
W2172132693 cites W2100837269 @default.
W2172132693 cites W2131443627 @default.
W2172132693 cites W2134155634 @default.
W2172132693 cites W2134282794 @default.
W2172132693 cites W2143241514 @default.
W2172132693 cites W2149426905 @default.
W2172132693 cites W2163505613 @default.
W2172132693 cites W2164015929 @default.
W2172132693 cites W2167075350 @default.
W2172132693 cites W2171226274 @default.
W2172132693 cites W4229958257 @default.
W2172132693 doi "https://doi.org/10.1074/jbc.m104301200" @default.
W2172132693 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/11696534" @default.
W2172132693 hasPublicationYear "2002" @default.
W2172132693 type Work @default.
W2172132693 sameAs 2172132693 @default.
W2172132693 citedByCount "100" @default.
W2172132693 countsByYear W21721326932012 @default.
W2172132693 countsByYear W21721326932013 @default.
W2172132693 countsByYear W21721326932014 @default.
W2172132693 countsByYear W21721326932015 @default.
W2172132693 countsByYear W21721326932016 @default.
W2172132693 countsByYear W21721326932017 @default.
W2172132693 countsByYear W21721326932018 @default.
W2172132693 countsByYear W21721326932019 @default.
W2172132693 countsByYear W21721326932020 @default.
W2172132693 countsByYear W21721326932021 @default.
W2172132693 crossrefType "journal-article" @default.
W2172132693 hasAuthorship W2172132693A5003630359 @default.
W2172132693 hasAuthorship W2172132693A5010145586 @default.
W2172132693 hasAuthorship W2172132693A5016617567 @default.
W2172132693 hasAuthorship W2172132693A5017407991 @default.
W2172132693 hasAuthorship W2172132693A5017450232 @default.
W2172132693 hasAuthorship W2172132693A5029861032 @default.
W2172132693 hasAuthorship W2172132693A5035702067 @default.
W2172132693 hasAuthorship W2172132693A5036241830 @default.
W2172132693 hasAuthorship W2172132693A5037246488 @default.
W2172132693 hasAuthorship W2172132693A5045416314 @default.
W2172132693 hasAuthorship W2172132693A5050708630 @default.
W2172132693 hasAuthorship W2172132693A5063952385 @default.
W2172132693 hasAuthorship W2172132693A5066393135 @default.
W2172132693 hasAuthorship W2172132693A5076422953 @default.
W2172132693 hasAuthorship W2172132693A5081550907 @default.
W2172132693 hasAuthorship W2172132693A5084885924 @default.
W2172132693 hasAuthorship W2172132693A5086129270 @default.
W2172132693 hasAuthorship W2172132693A5086674835 @default.
W2172132693 hasBestOaLocation W21721326931 @default.
W2172132693 hasConcept C104317684 @default.
W2172132693 hasConcept C127078168 @default.
W2172132693 hasConcept C1292079 @default.
W2172132693 hasConcept C170493617 @default.
W2172132693 hasConcept C183481951 @default.