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This Article Full Text Full Text (PDF) All Versions of this Article: 286/5/G722    most recent 00411.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (19) Citing Articles via Google Scholar Google Scholar Articles by Sung, C. K. Articles by Tsukamoto, H. Search for Related Content PubMed PubMed Citation Articles by Sung, C. K. Articles by Tsukamoto, H.

LIVER AND BILIARY TRACT

Tumor necrosis factor- inhibits peroxisome proliferator-activated receptor activity at a posttranslational level in hepatic stellate cells

¹Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles 90089–9141; and ²Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073

Submitted 18 September 2003 ; accepted in final form 1 December 2003

Diminished activity of peroxisome proliferator-activated receptor (PPAR) is implicated in activation of hepatic stellate cells (HSC), a critical event in the development of liver fibrosis. In the present study, we investigated PPAR regulation by TNF- in an HSC line designated as BSC. In BSC, TNF- decreased both basal and ligand (GW1929)-induced PPAR mRNA levels without changing its protein expression. Nuclear extracts from BSC treated with TNF- showed decreased binding of PPAR to PPAR-responsive element (PPRE) as determined by electrophoretic mobility shift assay. In BSC transiently transfected with a PPAR1 expression vector and a PPRE-luciferase reporter gene, TNF- decreased both basal and GW1929-induced transactivation of the PPRE promoter. TNF- increased activation of ERK1/2 and JNK, previously implicated in phosphorylation of Ser⁸² of PPAR1 and resultant negative regulation of PPAR transactivity. In fact, TNF- failed to inhibit transactivity of a Ser⁸²Ala PPAR1 mutant in BSC. TNF--mediated inhibition of PPAR transactivity was not blocked with a Ser³²Ala/Ser³⁶Ala mutant of inhibitory NF-B (IB). These results suggest that TNF- inhibits PPAR transactivity in cultured HSC, at least in part, by diminished PPAR-PPRE (DNA) binding and ERK1/2-mediated phosphorylation of Ser⁸² of PPAR1, but not via the NF-B pathway.

perisinusoidal pericytes; peroxisome proliferator-activated receptor response element; extracellular signal-regulated kinase 1/2

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