AJP - Gastrointestinal and Liver Physiology, Vol 272, Issue 3 589-G596, Copyright © 1997 by American Physiological Society

ARTICLES

Diminished retinoic acid signaling in hepatic stellate cells in cholestatic liver fibrosis

M. Ohata, M. Lin, M. Satre and H. Tsukamoto
Division of Gastrointestinal and Liver Diseases, University of Southern California School of Medicine and Veterans Affairs Outpatient Clinic, Los Angeles 90033-4581, USA.

Hepatic stellate cells (HSC) participate in liver fibrogenesis via myofibroblastic activation, the extent of which appears to correlate with the loss of cellular vitamin A. The present study has tested a hypothesis that HSC activation is associated with diminished retinoic acid (RA) signaling. Pure HSC were isolated from rats with cholestatic liver fibrosis induced by bile duct ligation (BDL) and sham-operated animals (Sham). Northern blot analysis of HSC RNA from BDL confirmed fibrogenic activation of the cells with enhanced mRNA levels for procollagen-alpha1(I) and transforming growth factor-beta1 (TGF-beta1). Competitive polymerase chain reaction analysis showed selective reductions in the mRNA levels of RA receptor (RAR)-beta and retinoid X receptor (RXR)-alpha to 20 and 17% of the Sham HSC. The mRNA level for cellular retinol binding protein I, a gene with RA responsive element (RARE), was also suppressed by 78% in BDL. The concentrations of all-trans-RA and 9-cis-RA were decreased in HSC from BDL. Nuclear extracts of these cells showed diminished binding activity to the RARE, whereas activity of AP-1, a transcription factor known to be antagonized by RAR and RXR, was enhanced. These results demonstrate diminished RA signaling in HSC from cholestatic liver fibrosis, which appeared to have resulted from RA deficiency and suppressed expression of RAR-beta and RXR-alpha. Furthermore, the reciprocal enhancement of AP-1 activity and coordinately increased expression of an AP-1 responsive gene, TGF-beta1, suggest a permissive role of the diminished RA signaling in promoting AP-1 activity and TGF-beta1 expression.

This article has been cited by other articles:

				S. L. Friedman Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver Physiol Rev, January 1, 2008; 88(1): 125 - 172. [Abstract] [Full Text] [PDF]

				S. Radaeva, L. Wang, S. Radaev, W.-I. Jeong, O. Park, and B. Gao Retinoic acid signaling sensitizes hepatic stellate cells to NK cell killing via upregulation of NK cell activating ligand RAE1 Am J Physiol Gastrointest Liver Physiol, October 1, 2007; 293(4): G809 - G816. [Abstract] [Full Text] [PDF]

				M. Trauner and J. L. Boyer Bile Salt Transporters: Molecular Characterization, Function, and Regulation Physiol Rev, April 1, 2003; 83(2): 633 - 671. [Abstract] [Full Text] [PDF]

				K. Hellemans, K. Rombouts, E. Quartier, A. S. Dittie, A. Knorr, L. Michalik, V. Rogiers, F. Schuit, W. Wahli, and A. Geerts PPAR{beta} regulates vitamin A metabolism-related gene expression in hepatic stellate cells undergoing activation J. Lipid Res., February 1, 2003; 44(2): 280 - 295. [Abstract] [Full Text] [PDF]

				P. Mathurin, S. Xiong, K. K. Kharbanda, N. Veal, T. Miyahara, K. Motomura, R. A. Rippe, M. G. Bachem, and H. Tsukamoto IL-10 receptor and coreceptor expression in quiescent and activated hepatic stellate cells Am J Physiol Gastrointest Liver Physiol, June 1, 2002; 282(6): G981 - G990. [Abstract] [Full Text] [PDF]

				C. B. Stephensen, R. Rasooly, X. Jiang, M. A. Ceddia, C. T. Weaver, R. A. S. Chandraratna, and R. P. Bucy Vitamin A Enhances in Vitro Th2 Development Via Retinoid X Receptor Pathway J. Immunol., May 1, 2002; 168(9): 4495 - 4503. [Abstract] [Full Text] [PDF]

				K. Motomura, M. Ohata, M. Satre, and H. Tsukamoto Destabilization of TNF-{alpha} mRNA by retinoic acid in hepatic macrophages: implications for alcoholic liver disease Am J Physiol Endocrinol Metab, September 1, 2001; 281(3): E420 - E429. [Abstract] [Full Text] [PDF]

				A. Lang, L. W. Schrum, R. Schoonhoven, S. Tuvia, J. A. Solis-Herruzo, H. Tsukamoto, D. A. Brenner, and R. A. Rippe Expression of small heat shock protein alpha B-crystallin is induced after hepatic stellate cell activation Am J Physiol Gastrointest Liver Physiol, December 1, 2000; 279(6): G1333 - G1342. [Abstract] [Full Text] [PDF]

				S. Vogel, R. Piantedosi, J. Frank, A. Lalazar, D. C. Rockey, S. L. Friedman, and W. S. Blaner An immortalized rat liver stellate cell line (HSC-T6): a new cell model for the study of retinoid metabolism in vitro J. Lipid Res., June 1, 2000; 41(6): 882 - 893. [Abstract] [Full Text]

				L. A. Denson, K. L. Auld, D. S. Schiek, M. H. McClure, D. J. Mangelsdorf, and S. J. Karpen Interleukin-1beta Suppresses Retinoid Transactivation of Two Hepatic Transporter Genes Involved in Bile Formation J. Biol. Chem., March 17, 2000; 275(12): 8835 - 8843. [Abstract] [Full Text] [PDF]

				H. Tsukamoto, M. Lin, M. Ohata, C. Giulivi, S. W. French, and G. Brittenham Iron primes hepatic macrophages for NF-kappa B activation in alcoholic liver injury Am J Physiol Gastrointest Liver Physiol, December 1, 1999; 277(6): G1240 - G1250. [Abstract] [Full Text] [PDF]

				K Hellemans, I Grinko, K Rombouts, D Schuppan, and A Geerts All-trans and 9-cis retinoic acid alter rat hepatic stellate cell phenotype differentially Gut, July 1, 1999; 45(1): 134 - 142. [Abstract] [Full Text] [PDF]

				S. C. Wang, M. Ohata, L. Schrum, R. A. Rippe, and H. Tsukamoto Expression of Interleukin-10 by in Vitro and in Vivo Activated Hepatic Stellate Cells J. Biol. Chem., January 2, 1998; 273(1): 302 - 308. [Abstract] [Full Text] [PDF]

				T. Miyahara, L. Schrum, R. Rippe, S. Xiong, H. F. Yee Jr., K. Motomura, F. A. Anania, T. M. Willson, and H. Tsukamoto Peroxisome Proliferator-activated Receptors and Hepatic Stellate Cell Activation J. Biol. Chem., November 10, 2000; 275(46): 35715 - 35722. [Abstract] [Full Text] [PDF]