Peroxisome Proliferator-activated Receptors and Hepatic Stellate Cell Activation

Abstract

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␥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 transcriptasepolymerase 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 culturedactivated HSC with ligands for PPAR␥ (10 M 15-deoxy-⌬ 12,14 -PGJ 2 (15dPGJ 2 ); 0.1ϳ10 M 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 PPAR␥ antagonist (GW9662). HSC DNA and collagen synthesis were inhibited by WY14643 at the concentrations known to activate both PPAR␣ and ␥ (>100 M) but not at those that only activate PPAR␣ (<10 M) or by a synthetic PPAR␣-selective agonist (GW9578). 15dPGJ 2 reduced ␣1(I) procollagen, smooth muscle ␣-actin, and monocyte chemotactic protein-1 mRNA levels while inducing matrix metalloproteinase-3 and CD36. 15dPGJ 2 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 15dPGJ 2 . 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.

Peroxisome proliferator-activated receptor γ ligand-induced growth inhibition of human hepatocellular carcinoma

“…PPARγ ligands exhibited a marked growth inhibitory potential on hepatocellular carcinoma cells through induction of G1 cell cycle arrest and recent studies have also shown that activation of PPARγ can inhibit the profibrogenic and proinflammatory actions of hepatic stellate cells (Galli et al, 2000;Marra et al, 2000;Miyahara et al, 2000). Taken together, we conclude that PPARγ ligands may also prove beneficial for primary or secondary chemoprevention of hepatocellular carcinoma.…”

Epigenetic Modifications in Hepatic Stellate Cells Contribute to Liver Fibrosis

“…Peroxisome proliferator-activated receptor gamma (PPAR-γ) has a predominant leadership among the adipogenic genes. In this process, suppression of PPAR-γ expression was demonstrated to be regulated in complicated epigenetic ways, which influences the secretion of chemokines and proteins from HSCs (Miyahara et al 2000). In the competition between adipogenic genes and myogenic genes, myogenic genes gain advantage, which induces the differentiation of adipogenic HSCs to myogenic HSCs.…”

Silibinin Inhibits Proliferation and Migration of Human Hepatic Stellate LX-2 Cells

“…12 Treatment of culture activated HSCs with PPAR-g ligands reversed its activation by inhibiting collagen production and blocking PPAR-g mediated cellular proliferation. 13 These results clearly indicate the role of PPAR-g in regulation of HSCs activation in liver fibrogenesis. cMyc is an oncoprotein, which prevents cell cycle progression by controlling the expression of p21 and p27 cyclin dependent kinase inhibitor (CDKI) proteins which are growth inhibitor signals.…”

“…12,13 Additionally, it has been shown that the treatment of culture activated HSCs with PPAR-g ligands reversed the collagen production and activation of HSCs. 13 These results show that increase in PPAR-g protein expression is high in nonproliferating quiescent cells, and it is a valid parameter in differentiating the quiescent from activated cells.…”

“…12,13 Additionally, it has been shown that the treatment of culture activated HSCs with PPAR-g ligands reversed the collagen production and activation of HSCs. 13 These results show that increase in PPAR-g protein expression is high in nonproliferating quiescent cells, and it is a valid parameter in differentiating the quiescent from activated cells. Interestingly, LX-2 cells treated with SBN shows normal expression of PPAR-g at higher concentrations and it increased the expression in lower concentrations as compared to DMSO treatment indicating the fact that LX-2 cells have not undergone the proliferative state, and they remain quiescent.…”