PMID- 10969082
OWN - NLM
STAT- MEDLINE
DCOM- 20001229
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 275
IP  - 46
DP  - 2000 Nov 17
TI  - Peroxisome proliferator-activated receptors and hepatic stellate cell activation.
PG  - 35715-22
AB  - 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 PPARgamma1 but 
      not that for the adipocyte-specific gamma2 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 PPARgamma mRNA level in HSC from BDL. Nuclear extracts from BDL 
      cells showed an expected diminution of binding to PPAR-responsive element, 
      whereas NF-kappaB and AP-1 binding were increased. Treatment of 
      cultured-activated HSC with ligands for PPARgamma (10 microm 
      15-deoxy-Delta(12,14)-PGJ(2) (15dPGJ(2)); 0.1 approximately 10 microm BRL49653) 
      inhibited DNA and collagen synthesis without affecting the cell viability. 
      Suppression of HSC collagen by 15dPGJ(2) was abrogated 70% by the concomitant 
      treatment with a PPARgamma antagonist (GW9662). HSC DNA and collagen synthesis 
      were inhibited by WY14643 at the concentrations known to activate both PPARalpha 
      and gamma (>100 microm) but not at those that only activate PPARalpha (<10 
      microm) or by a synthetic PPARalpha-selective agonist (GW9578). 15dPGJ(2) reduced 
      alpha1(I) procollagen, smooth muscle alpha-actin, and monocyte chemotactic 
      protein-1 mRNA levels while inducing matrix metalloproteinase-3 and CD36. 
      15dPGJ(2) and BRL49653 inhibited alpha1(I) procollagen promoter activity. Tumor 
      necrosis factor alpha (10 ng/ml) reduced PPARgamma mRNA, and this effect was 
      prevented by the treatment with 15dPGJ(2). These results demonstrate that HSC 
      activation is associated with the reductions in PPARgamma expression and 
      PPAR-responsive element binding in vivo and is reversed by the treatment with 
      PPARgamma ligands in vitro. These findings implicate diminished PPARgamma 
      signaling in molecular mechanisms underlying activation of HSC in liver 
      fibrogenesis and the potential therapeutic value of PPARgamma ligands for liver 
      fibrosis.
FAU - Miyahara, T
AU  - Miyahara T
AD  - Departments of Medicine and Pathology, Keck School of Medicine of the University 
      of Southern California, Los Angeles, California 90033, USA.
FAU - Schrum, L
AU  - Schrum L
FAU - Rippe, R
AU  - Rippe R
FAU - Xiong, S
AU  - Xiong S
FAU - Yee, H F Jr
AU  - Yee HF Jr
FAU - Motomura, K
AU  - Motomura K
FAU - Anania, F A
AU  - Anania FA
FAU - Willson, T M
AU  - Willson TM
FAU - Tsukamoto, H
AU  - Tsukamoto H
LA  - eng
GR  - AA10459/AA/NIAAA NIH HHS/United States
GR  - DK02450/DK/NIDDK NIH HHS/United States
GR  - R37-AA06603/AA/NIAAA NIH HHS/United States
GR  - etc.
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (15-deoxy-delta(12,14)-prostaglandin J2)
RN  - 0 (Protein Isoforms)
RN  - 0 (Pyrimidines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Thiazoles)
RN  - 0 (Thiazolidinediones)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 05V02F2KDG (Rosiglitazone)
RN  - 86C4MRT55A (pirinixic acid)
RN  - 9007-34-5 (Collagen)
RN  - 9007-49-2 (DNA)
RN  - RXY07S6CZ2 (Prostaglandin D2)
SB  - IM
MH  - Animals
MH  - Cell Size/drug effects
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Collagen/biosynthesis/genetics
MH  - DNA/biosynthesis
MH  - Gene Expression Regulation/drug effects
MH  - Liver/*cytology/drug effects/*metabolism/pathology
MH  - Liver Cirrhosis, Biliary/genetics/metabolism/pathology
MH  - Liver Cirrhosis, Experimental/genetics/metabolism/pathology
MH  - Male
MH  - Promoter Regions, Genetic/genetics
MH  - Prostaglandin D2/analogs & derivatives/pharmacology
MH  - Protein Binding
MH  - Protein Isoforms/agonists/genetics/metabolism
MH  - Pyrimidines/pharmacology
MH  - RNA, Messenger/genetics/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Receptors, Cytoplasmic and Nuclear/agonists/genetics/*metabolism
MH  - Rosiglitazone
MH  - Thiazoles/pharmacology
MH  - *Thiazolidinediones
MH  - Transcription Factors/agonists/genetics/*metabolism
MH  - Tumor Necrosis Factor-alpha/antagonists & inhibitors/pharmacology
EDAT- 2000/09/02 11:00
MHDA- 2001/02/28 10:01
CRDT- 2000/09/02 11:00
PHST- 2000/09/02 11:00 [pubmed]
PHST- 2001/02/28 10:01 [medline]
PHST- 2000/09/02 11:00 [entrez]
AID - S0021-9258(20)88662-1 [pii]
AID - 10.1074/jbc.M006577200 [doi]
PST - ppublish
SO  - J Biol Chem. 2000 Nov 17;275(46):35715-22. doi: 10.1074/jbc.M006577200.