Key points are not available for this paper at this time.
Inhibition of peroxisome proliferator-activated receptor γ (PPARγ) function by TNF-α contributes to glucose and fatty acid metabolic disorders in inflammation and cancer, although the molecular mechanism is not fully understood. In this study, we demonstrate that nuclear translocation of HDAC3 is regulated by TNF-α, and this event is required for inhibition of transcriptional activity of PPARγ by TNF-α. HDAC3 is associated with IκBα in the cytoplasm. After IκBα degradation in response to TNF-α, HDAC3 is subject to nuclear translocation, leading to an increase in HDAC3 activity in the nucleus. This event leads to subcellular redistribution of HDAC3. Knock-out of IκBα, but not p65 or p50, leads to disappearance of HDAC3 in the cytoplasm, which is associated with HDAC3 enrichment in the nucleus. These data suggest that inhibition of PPARγ by TNF-α is not associated with a reduction in the DNA binding activity of PPARγ. Rather, these results suggest that IκBα-dependent nuclear translocation of HDAC3 is responsible for PPARγ inhibition by TNF-α. Inhibition of peroxisome proliferator-activated receptor γ (PPARγ) function by TNF-α contributes to glucose and fatty acid metabolic disorders in inflammation and cancer, although the molecular mechanism is not fully understood. In this study, we demonstrate that nuclear translocation of HDAC3 is regulated by TNF-α, and this event is required for inhibition of transcriptional activity of PPARγ by TNF-α. HDAC3 is associated with IκBα in the cytoplasm. After IκBα degradation in response to TNF-α, HDAC3 is subject to nuclear translocation, leading to an increase in HDAC3 activity in the nucleus. This event leads to subcellular redistribution of HDAC3. Knock-out of IκBα, but not p65 or p50, leads to disappearance of HDAC3 in the cytoplasm, which is associated with HDAC3 enrichment in the nucleus. These data suggest that inhibition of PPARγ by TNF-α is not associated with a reduction in the DNA binding activity of PPARγ. Rather, these results suggest that IκBα-dependent nuclear translocation of HDAC3 is responsible for PPARγ inhibition by TNF-α. PPARγ is a nuclear receptor in the family of peroxisome proliferator-activated receptor (PPAR) 2The abbreviations used are: PPAR, peroxisome proliferator-activated receptor; TNF, tumor necrosis factor; HDAC, histone deacetylase; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; EMSA, electrophoretic mobility shift assay; HEK, human embryonic kidney; ChIP, chromatin immunoprecipitation assay; WT, wild type; GFP, green fluorescent protein; IL, interleukin; ssIκBα, supersuppressor IκBα; RXR, retinoid X receptor; SMRT, silencing mediator for retinoic and thyroid hormone receptors; NCoR, nuclear corepressor; Trog, troglitazone; RT, reverse transcriptase. that includes PPARα, PPARγ, and PPARδ (PPARβ) (reviewed in Refs. 1.Spiegelman B.M. Diabetes. 1998; 47: 507-514Crossref PubMed Scopus (1655) Google Scholar and 2.Berger J. Moller D.E. Annu. Rev. Med. 2002; 53: 409-435Crossref PubMed Scopus (2159) Google Scholar). PPARγ is a master transcriptional regulator of lipid and glucose metabolism (reviewed in Refs. 1.Spiegelman B.M. Diabetes. 1998; 47: 507-514Crossref PubMed Scopus (1655) Google Scholar, 2.Berger J. Moller D.E. Annu. Rev. Med. 2002; 53: 409-435Crossref PubMed Scopus (2159) Google Scholar, 3.Lazar M.A. Nat. Med. 2001; 7: 23-24Crossref PubMed Scopus (54) Google Scholar). Inhibition of PPARγ function by inflammatory cytokines may contribute to the loss of insulin sensitivity in obese subjects and loss of fat storage in cancer patients under cachexia. Although TNF-α is known to inhibit the ligand-dependent transcriptional activity of PPARγ, the precise mechanism remains to be fully understood (4.Hu E. Kim J.B. Sarraf P. Spiegelman B.M. Science. 1996; 274: 2100-2103Crossref PubMed Scopus (949) Google Scholar, 5.Zhang B. Berger J. Hu E. Szalkowski D. White-Carrington S. Spiegelman B.M. Moller D.E. Mol. Endocrinol. 1996; 10: 1457-1466Crossref PubMed Scopus (317) Google Scholar, 6.Ruan H. Hacohen N. Golub T.R. Van Parijs L. Lodish H.F. Diabetes. 2002; 51: 1319-1336Crossref PubMed Scopus (434) Google Scholar, 7.Suzawa, M., Takada, I., Yanagisawa, J., Ohtake, F., Ogawa, S., Yamauchi, T., Kadowaki, T., Takeuchi, Y., Shibuya, H., Gotoh, Y., Matsumoto, K., and Kato, S. (2003) Nat. Cell Biol.Google Scholar, 8.Ruan H. Pownall H.J. Lodish H.F. J. Biol. Chem. 2003; 278: 28181-28192Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). In this study, we addressed this issue by analyzing the molecular mechanism of TNF-α action on PPARγ. The transcriptional activity of PPARγ is controlled by DNA binding activity and nuclear receptor cofactors that include corepressors and coactivators. PPARs form heterodimers with the retinoid X receptor (RXR), which is activated by 9-cis retinoic acid (9.Tontonoz P. Graves R.A. Budavari A.I. Erdjument-Bromage H. Lui M. Hu E. Tempst P. Spiegelman B.M. Nucleic Acids Res. 1994; 22: 5628-5634Crossref PubMed Scopus (335) Google Scholar). It is generally believed that the heterodimer is associated with the nuclear receptor corepressor complex in the absence of PPARγ ligand. Upon activation by a ligand, the corepressor complex is replaced by coactivators leading to transcriptional initiation of target genes. The corepressor for PPARγ is a protein complex containing HDAC3 (histone deacetylase 3) and SMRT (silencing mediator for retinoic and thyroid hormone receptors) or NCoR (nuclear corepressor). RIP140 (receptor-interacting protein) may also be a component in the corepressor complex (10.Hu X. Li Y. Lazar M.A. Mol. Cell Biol. 2001; 21: 1747-1758Crossref PubMed Scopus (117) Google Scholar, 11.Zamir I. Zhang J. Lazar M.A. Genes Dev. 1997; 11: 835-846Crossref PubMed Scopus (204) Google Scholar, 12.Krogsdam A.M. Nielsen C.A. Neve S. Holst D. Helledie T. Thomsen B. Bendixen C. Mandrup S. Kristiansen K. Biochem. 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Diabetes. 2002; 51: 1319-1336Crossref PubMed Scopus (434) Google Scholar). This is in with TNF-α for or PPARγ is not and the inhibition is in with a PPARγ (4.Hu E. Kim J.B. Sarraf P. Spiegelman B.M. Science. 1996; 274: 2100-2103Crossref PubMed Scopus (949) Google Scholar, 7.Suzawa, M., Takada, I., Yanagisawa, J., Ohtake, F., Ogawa, S., Yamauchi, T., Kadowaki, T., Takeuchi, Y., Shibuya, H., Gotoh, Y., Matsumoto, K., and Kato, S. (2003) Nat. Cell Biol.Google Scholar, 8.Ruan H. Pownall H.J. Lodish H.F. J. Biol. Chem. 2003; 278: 28181-28192Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). In the the ligand-dependent transcriptional activity of PPARγ is as a of loss of DNA binding of inhibition on activation of as the TNF-α activity by the IκBα H. Hacohen N. Golub T.R. Van Parijs L. Lodish H.F. Diabetes. 2002; 51: 1319-1336Crossref PubMed Scopus (434) Google Scholar). is a that in the in the absence of It is generally believed that IκBα by in the (reviewed in Ref. M. 1999; PubMed Scopus Google Scholar). IκBα degradation is controlled by a and mechanism that is by activation of M. Y. Annu. Rev. PubMed Scopus Google Scholar). In the TNF-α although and N-terminal to inhibit the transcriptional activity of PPARγ of in the PPARγ protein M. D. Lazar M.A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, T. 1999; PubMed Scopus Google Scholar), the of these protein remains to be In this study, inhibition of the transcriptional activity of PPARγ is with a on results demonstrate that IκBα the nuclear translocation of which is required for the of PPARγ activity by TNF-α. This a new mechanism by which TNF-α PPARγ activity by the nuclear receptor the In this the is by the of The by of the of the I. R.G. S. J. 11: PubMed Scopus Google the of for and X. J.M. N. J. 2001; PubMed Scopus Google Scholar, D. M. D. M. J. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Lee L. N. J. Biol. 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Cell Biol. 12: Google This of an of and a of The of the is in in which the DNA is in The for of protein The the The in the and for used as a for of the The of the used to the of with The or is in this In the PPARγ and of the used to the The data with Inhibition of PPARγ in is well known that TNF-α in and of PPARγ of a of for lipid and PPARγ a target in the for the molecular mechanism of TNF-α In to the inhibition of PPARγ TNF-α may the transcriptional activity of PPARγ of PPARγ by activation of or (4.Hu E. Kim J.B. Sarraf P. Spiegelman B.M. Science. 1996; 274: 2100-2103Crossref PubMed Scopus (949) Google Scholar, M. D. Lazar M.A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, T. 1999; PubMed Scopus Google Scholar, J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google and of DNA binding of PPARγ by activation of M., Takada, I., Yanagisawa, J., Ohtake, F., Ogawa, S., Yamauchi, T., Kadowaki, T., Takeuchi, Y., Shibuya, H., Gotoh, Y., Matsumoto, K., and Kato, S. (2003) Nat. Cell Biol.Google Scholar). In the of PPARγ TNF-α activity in this with a on the of The a PPARγ in the of in which the activity by the TNF-α to reduction in the PPARγ The reduction by of the ssIκBα, a of IκBα TNF-α replaced by in the is not these results suggest that the TNF-α activity is on degradation of the IκBα In of this the that IκBα degradation also activity of TNF-α or The and a that the function of IκBα is not by to the activity in the absence of TNF-α the molecular of activity in this in TNF-α by PPARγ is regulated by such as the of nuclear receptor and the DNA binding activity of PPARγ. The is by the corepressor that is of or The corepressor is associated with PPARγ in the absence of PPARγ Lazar M.A. Mol. Biol. 2001; 21: PubMed Scopus Google Scholar, T. M. Lazar M.A. Genes Dev. PubMed Scopus Google Scholar). PPARγ function is IκBα the DNA binding activity of PPARγ the The the nuclear of with PPARγ. The results that the PPARγ DNA binding activity not by TNF-α or that the of PPARγ activity by TNF-α is not a of loss of DNA binding not the DNA binding the of PPARγ activity by in the absence of TNF-α may be a These data suggest that TNF-α PPARγ function a mechanism of DNA The of the complex in and the of the corepressor we SMRT, and NCoR with The and of the used in by the target protein in the T. Lazar M.A. Mol. Cell Biol. 2003; PubMed Scopus Google Scholar, C. S. Zhang X. E. D. J. 2003; PubMed Scopus Google Scholar, P. Zhang X. Zhang X. Lazar M. E. H. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The data for HDAC3 as an to that is in this the results for SMRT, and NCoR not on HDAC3 and SMRT in this with of these Inhibition of HDAC3 or SMRT to of TNF-α activity in the of PPARγ that HDAC3 and SMRT the corepressor for PPARγ. in NCoR also to of PPARγ the inhibition of and to the inhibition of the corepressor protein SMRT, or NCoR to of PPARγ the data suggest that inhibition of PPARγ is on the corepressor TNF-α of the to is believed that of the corepressor with PPARγ is required for inhibition of the transcriptional activity of PPARγ. The data suggest that TNF-α may by of the corepressor to PPARγ. this the of the corepressors with PPARγ in the the In the of HDAC3 in the This of TNF-α by Trog, which the HDAC3 and the for an of the SMRT also by TNF-α and the increase also by This of that TNF-α of the corepressor with PPARγ. Although the corepressor by TNF-α, the DNA binding activity of PPARγ not or In the DNA binding activity of PPARγ in the nuclear to that in reduction for PPARγ These data the that but not DNA in PPARγ inhibition by TNF-α. HDAC3 a of the data suggest that the of HDAC3 and SMRT may be responsible for PPARγ inhibition by TNF-α. that the be to IκBα degradation TNF-α activity by IκBα degradation may contribute to the of corepressors by protein or of these the protein for HDAC3 and SMRT in the of not a in the protein TNF-α The of HDAC3 and SMRT by protein in and nuclear the HDAC3 protein in and nuclear the HDAC3 in the cytoplasm, but in nuclear a and HDAC3 in the subcellular a of nuclear translocation in the of HDAC3 The of HDAC3 in the is to that of HDAC3 in the which in the In the and SMRT in the and subcellular not by TNF-α to these we that HDAC3 be in the inhibition of PPARγ by TNF-α. HDAC3 translocation may be controlled by IκBα TNF-α activity is on IκBα this the on the nuclear translocation may be a of IκBα The of HDAC3 with IκBα The the of HDAC3 in the immunoprecipitation of IκBα and IκBα in the immunoprecipitation of HDAC3 These data suggest that IκBα and HDAC3 in the protein complex in in this SMRT not in the immunoprecipitation of IκBα or that HDAC3 not with SMRT in the cytoplasm. This is with the that SMRT not in the IκBα of of may be of HDAC3 in the cytoplasm. this is HDAC3 in the in the absence of this with the in this In the the HDAC3 protein in and nuclear by and the in HDAC3 associated with IκBα degradation to the in the cytoplasm, HDAC3 in the nucleus. This by nuclear translocation of p65 a not in the cytoplasm, and not in the TNF-α In the HDAC3 protein not in the and but in the nuclear The nuclear of HDAC3 that of In TNF-α to increase the nuclear of HDAC3. The data suggest that IκBα is required for the of HDAC3. In the This that IκBα also not in the of PPARγ not The of the and nuclear is by the such as in the and in the nucleus. of HDAC3 in by of of HDAC3 by IκBα a protein In the in and nuclear with a in the by of In of in the and not in the cytoplasm. of to in the and an increase in the cytoplasm. These data the of IκBα in the of subcellular of HDAC3. IκBα activity also in that with The of HDAC3 in the in to the This associated with a in nuclear HDAC3. nuclear translocation of HDAC3 not in this the data that IκBα nuclear translocation of HDAC3. in suggest that be to PPARγ function by HDAC3 to PPARγ. this is the an lipid and to the activity of TNF-α. these in the and in the absence or of TNF-α. TNF-α, well to the the lipid in the as in the under the In the of TNF-α, of not as by the of molecular of such as PPARγ, and of these by TNF-α in but not in that to TNF-α. In this study, to TNF-α the of for This to inhibition of PPARγ protein as by protein that TNF-α may of of PPARγ This activity of TNF-α be on activation of the inhibition of the by leads to to TNF-α. HDAC3 translocation may contribute to this TNF-α inhibition of the ligand-dependent activity of PPARγ, the of HDAC3 and PPARγ in the In the absence of TNF-α, the in the but in the In the of the by TNF-α in In the the The in to the that in but not in The DNA binding activity of PPARγ not by TNF-α in as PPARγ not nuclear translocation of HDAC3 by ssIκBα, these results suggest that in HDAC3 translocation is responsible for the HDAC3 and PPARγ, and is to the translocation by TNF-α. The of HDAC3 and PPARγ is in the transcriptional of the PPARγ target is a well established target for PPARγ. by TNF-α in the but not in the that HDAC3 is required for inhibition of PPARγ target these data suggest that the TNF-α in the inhibition of and In the inhibition of TNF-α of PPARγ leading to a of PPARγ In the TNF-α inhibition of the ligand-dependent PPARγ translocation of HDAC3 is required for the activity of TNF-α. HDAC3 translocation may be in IκBα degradation is required in is a of PPARγ TNF-α is to that to the ligand-dependent activity of PPARγ. of the ERK, and to inhibit (4.Hu E. Kim J.B. Sarraf P. Spiegelman B.M. Science. 1996; 274: 2100-2103Crossref PubMed Scopus (949) Google Scholar, 7.Suzawa, M., Takada, I., Yanagisawa, J., Ohtake, F., Ogawa, S., Yamauchi, T., Kadowaki, T., Takeuchi, Y., Shibuya, H., Gotoh, Y., Matsumoto, K., and Kato, S. (2003) Nat. Cell Biol.Google Scholar, 8.Ruan H. Pownall H.J. Lodish H.F. J. Biol. 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The of of HDAC3 not in These data suggest that p65 and not required for HDAC3 in In TNF-α PPARγ activity is on inhibition of PPARγ The is of the transcriptional activity of PPARγ by nuclear IκBα of corepressor function may be required in In this study, TNF-α is to inhibit the transcriptional activity of PPARγ a in which DNA binding activity of PPARγ is not IκBα an in this by nuclear translocation of HDAC3. also a new function for and for a Lazar the of the of the of the
Gao et al. (Thu,) studied this question.