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Tumor necrosis factor-alpha inhibits peroxisome proliferator-activated receptor gamma activity at a posttranslational level in hepatic stellate cells.
Am J Physiol Gastrointest Liver Physiol. 2004 May; 286(5):G722-9.AJ

Abstract

Diminished activity of peroxisome proliferator-activated receptor gamma (PPARgamma) is implicated in activation of hepatic stellate cells (HSC), a critical event in the development of liver fibrosis. In the present study, we investigated PPARgamma regulation by TNF-alpha in an HSC line designated as BSC. In BSC, TNF-alpha decreased both basal and ligand (GW1929)-induced PPARgamma mRNA levels without changing its protein expression. Nuclear extracts from BSC treated with TNF-alpha showed decreased binding of PPARgamma to PPAR-responsive element (PPRE) as determined by electrophoretic mobility shift assay. In BSC transiently transfected with a PPARgamma1 expression vector and a PPRE-luciferase reporter gene, TNF-alpha decreased both basal and GW1929-induced transactivation of the PPRE promoter. TNF-alpha increased activation of ERK1/2 and JNK, previously implicated in phosphorylation of Ser(82) of PPARgamma1 and resultant negative regulation of PPARgamma transactivity. In fact, TNF-alpha failed to inhibit transactivity of a Ser(82)Ala PPARgamma1 mutant in BSC. TNF-alpha-mediated inhibition of PPARgamma transactivity was not blocked with a Ser(32)Ala/Ser(36)Ala mutant of inhibitory NF-kappaBalpha (IkappaBalpha). These results suggest that TNF-alpha inhibits PPARgamma transactivity in cultured HSC, at least in part, by diminished PPARgamma-PPRE (DNA) binding and ERK1/2-mediated phosphorylation of Ser(82) of PPARgamma1, but not via the NF-kappaB pathway.

Authors+Show Affiliations

Dept. of Pathology, Keck School of Medicine of the Univ. of Southern California, 1333 San Pablo St., MMR 412, Los Angeles, CA 90089-9141, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14656714

Citation

Sung, Chin K., et al. "Tumor Necrosis Factor-alpha Inhibits Peroxisome Proliferator-activated Receptor Gamma Activity at a Posttranslational Level in Hepatic Stellate Cells." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 286, no. 5, 2004, pp. G722-9.
Sung CK, She H, Xiong S, et al. Tumor necrosis factor-alpha inhibits peroxisome proliferator-activated receptor gamma activity at a posttranslational level in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2004;286(5):G722-9.
Sung, C. K., She, H., Xiong, S., & Tsukamoto, H. (2004). Tumor necrosis factor-alpha inhibits peroxisome proliferator-activated receptor gamma activity at a posttranslational level in hepatic stellate cells. American Journal of Physiology. Gastrointestinal and Liver Physiology, 286(5), G722-9.
Sung CK, et al. Tumor Necrosis Factor-alpha Inhibits Peroxisome Proliferator-activated Receptor Gamma Activity at a Posttranslational Level in Hepatic Stellate Cells. Am J Physiol Gastrointest Liver Physiol. 2004;286(5):G722-9. PubMed PMID: 14656714.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tumor necrosis factor-alpha inhibits peroxisome proliferator-activated receptor gamma activity at a posttranslational level in hepatic stellate cells. AU - Sung,Chin K, AU - She,Hongyun, AU - Xiong,Shigang, AU - Tsukamoto,Hidekazu, Y1 - 2003/12/04/ PY - 2003/12/6/pubmed PY - 2004/5/22/medline PY - 2003/12/6/entrez SP - G722 EP - 9 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am J Physiol Gastrointest Liver Physiol VL - 286 IS - 5 N2 - Diminished activity of peroxisome proliferator-activated receptor gamma (PPARgamma) is implicated in activation of hepatic stellate cells (HSC), a critical event in the development of liver fibrosis. In the present study, we investigated PPARgamma regulation by TNF-alpha in an HSC line designated as BSC. In BSC, TNF-alpha decreased both basal and ligand (GW1929)-induced PPARgamma mRNA levels without changing its protein expression. Nuclear extracts from BSC treated with TNF-alpha showed decreased binding of PPARgamma to PPAR-responsive element (PPRE) as determined by electrophoretic mobility shift assay. In BSC transiently transfected with a PPARgamma1 expression vector and a PPRE-luciferase reporter gene, TNF-alpha decreased both basal and GW1929-induced transactivation of the PPRE promoter. TNF-alpha increased activation of ERK1/2 and JNK, previously implicated in phosphorylation of Ser(82) of PPARgamma1 and resultant negative regulation of PPARgamma transactivity. In fact, TNF-alpha failed to inhibit transactivity of a Ser(82)Ala PPARgamma1 mutant in BSC. TNF-alpha-mediated inhibition of PPARgamma transactivity was not blocked with a Ser(32)Ala/Ser(36)Ala mutant of inhibitory NF-kappaBalpha (IkappaBalpha). These results suggest that TNF-alpha inhibits PPARgamma transactivity in cultured HSC, at least in part, by diminished PPARgamma-PPRE (DNA) binding and ERK1/2-mediated phosphorylation of Ser(82) of PPARgamma1, but not via the NF-kappaB pathway. SN - 0193-1857 UR - https://www.unboundmedicine.com/medline/citation/14656714/Tumor_necrosis_factor_alpha_inhibits_peroxisome_proliferator_activated_receptor_gamma_activity_at_a_posttranslational_level_in_hepatic_stellate_cells_ L2 - https://journals.physiology.org/doi/10.1152/ajpgi.00411.2003?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -