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J. Biol. Chem., Vol. 275, Issue 46, 35715-35722, November 17, 2000
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From the Departments of a Medicine and
b Pathology, Keck School of Medicine of the University
of Southern California, Los Angeles, California 90033, c Department of Veterans Affairs Greater Los Angeles
Healthcare System, Sepulveda, California 91343, Departments of
d Medicine and e Surgery, University of North
Carolina, Chapel Hill, North Carolina 27599-7038, f Departments of Medicine and Physiology, University
of California, Los Angeles, California 90095, g Department
of Medicine, University of Maryland, College Park, Maryland 21201, h Department of Medicinal Chemistry, Glaxo Wellcome Research
and Development,
Research Triangle Park, North Carolina 27709-3398
The present study examined the roles of
peroxisome proliferator-activated receptors (PPAR) in activation of
hepatic stellate cells (HSC), a pivotal event in liver fibrogenesis.
RNase protection assay detected mRNA for PPAR
Peroxisome Proliferator-activated Receptors and Hepatic
Stellate Cell Activation*
1 but not that for
the adipocyte-specific 2 isoform in HSC isolated from sham-operated
rats, whereas the transcripts for neither isoforms were detectable in
HSC from cholestatic liver fibrosis induced by bile duct ligation
(BDL). Semi-quantitative reverse transcriptase-polymerase chain
reaction confirmed a 70% reduction in PPAR mRNA level in HSC
from BDL. Nuclear extracts from BDL cells showed an expected diminution
of binding to PPAR-responsive element, whereas NF-
B and AP-1 binding
were increased. Treatment of cultured-activated HSC with ligands for
PPAR (10 µM
15-deoxy-
12,14-PGJ2 (15dPGJ2);
0.1~10 µM BRL49653) inhibited DNA and collagen synthesis without affecting the cell viability. Suppression of HSC
collagen by 15dPGJ2 was abrogated 70% by the concomitant
treatment with a PPAR antagonist (GW9662). HSC DNA and collagen
synthesis were inhibited by WY14643 at the concentrations known to
activate both PPAR
and (>100 µM) but not at those
that only activate PPAR (<10 µM) or by a synthetic
PPAR-selective agonist (GW9578). 15dPGJ2 reduced 1(I)
procollagen, smooth muscle -actin, and monocyte chemotactic
protein-1 mRNA levels while inducing matrix metalloproteinase-3 and
CD36. 15dPGJ2 and BRL49653 inhibited 1(I) procollagen
promoter activity. Tumor necrosis factor (10 ng/ml) reduced PPAR
mRNA, and this effect was prevented by the treatment with
15dPGJ2. These results demonstrate that HSC activation is associated with the reductions in PPAR expression and
PPAR-responsive element binding in vivo and is reversed by
the treatment with PPAR ligands in vitro. These findings
implicate diminished PPAR signaling in molecular mechanisms
underlying activation of HSC in liver fibrogenesis and the potential
therapeutic value of PPAR ligands for liver fibrosis.
*
This study was supported by National Institutes of Health
Grants R37-AA06603 (to H. T.), DK02450 (to H. Y.), DR34987 (to
R. P.), and AA10459 (to R. P.), University of Southern
California-UCLA Research Center for Alcoholic Liver and Pancreatic
Diseases Grant P50-AA11999, Molecular Biology and Tissue Culture Core
facilities of University of Southern California Research Center for
Liver Diseases Grant P30-DK48522, and a grant from the Medical Research Service of the Department of Veterans Affairs (to H. T.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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