Effect of peroxisome-proliferator activated receptor-γ on the regulation of leptin induced human hepatic stellate cell activation

Abstract

[한글]

렙틴(Leptin)은 간성상세포에 의한 간섬유화를 유도하는 인자로 알려진 반면, Peroxisome-proliferator activated receptor-γ (PPAR-γ)는 항섬유화 작용을 하는 물질로 알려져 있다. 그러나 간성상세포에서의 이 두 인자의 상호 관계에 대해서는 알려진 바가 없다. 이에 저자 등은 일반적인 분열촉진물질(mitogen)로 알려진 platelet derived growth factor (PDGF)와 렙틴으로 사람의 간성상세포를 활성화 시키고, PPAR-γ mRNA와 렙틴 수용체 mRNA의 발현 정도를 측정하였으며, PPAR-γ 배위자(ligand)를 처리한 후 이것이 각각의 mRNA 발현에 미치는 영향을 살펴 보았다.

1. PDGF와 마찬가지로 렙틴 또한 간성상세포의 활성화를 유발하였으며, PDGF와 렙틴에 의한 세포의 활성화는 PPAR-γ 배위자에 의해 억제되었다.

2. PDGF와 렙틴에 의해 활성화된 간성상세포에서 PPAR-γ mRNA의 발현이 감소되었으며, 이것은 PPAR-γ 배위자에 의해 어느 정도 회복되었다.

3. PDGF와 렙틴에 의해 활성화된 간성상세포에서 렙틴 수용체 mRNA의 발현이 증가되었으며, 이것은 PPAR-γ 배위자에 의해 감소되었다.

4. 간성상세포의 증식은 렙틴 수용체 mRNA 발현과는 양의 상관관계, 그리고 PPAR-γ mRNA 발현과는 음의 상관관계가 있었다.

5. 렙틴에 의한 간성상세포 활성화에 미치는 PPAR-γ의 효과는 extracellular factor regulated kinase (ERK) 활성화의 억제를 동반하였다. 반면, PDGF에 의해 활성화된 간성상세포에 미치는 PPAR-γ의 효과는 ERK 활성화의 억제와는 연관이 없었다.

결론적으로 PDGF와 렙틴에 의해 활성화된 간성상세포는 렙틴 수용체를 발현하는 세포이며, 렙틴 수용체 mRNA의 발현은 PPAR-γ의 의해 일부 조절될 수 있다.

[영문]Leptin is a peptide known to play a profibrogenic role in hepatic stellate cells (HSCs), when peroxisome-proliferator activated receptor (PPAR)-γ is suggested to have an anti-fibrogenic effect on HSCs. However, association of these two factors in HSC activation has not been demonstrated. We investigated the effect of ciglitazone, one of PPAR-γ ligands, on several parameters of leptin activated human HSCs as well as in platelet-derived growth factor (PDGF) activated cells. We hypothesized that PPAR-γ ligands would suppress leptin induced HSC activation, and that it had an inhibitory effect on leptin receptor mRNA expression. HSC proliferation was assessed by [3H]-thymidine incorporation assays. Messenger RNA expression of leptin receptor and PPAR-γ was evaluated by real time polymerase chain reaction (PCR). Expression of α-smooth muscle actin (SMA) and phosphorylated extracellular factor-regulated kinases (p-ERK) was detected by western blotting. Proliferation of human HSCs was achieved by both PDGF and leptin, and this could be suppressed by ciglitazone. PPAR-γ mRNA expression was diminished in HSCs, activated either by PDGF or leptin, and this was reversed by ciglitazone in both cases. Leptin receptor mRNA expression increased in HSCs activated either by PDGF or leptin, and the expression was inhibited by ciglitazone. Proliferation of HSCs had positive correlation with leptin receptor mRNA expression, and had negative correlation with PPAR-γ mRNA expression. HSC activation was induced by leptin and ciglitazone had a suppressive effect on this. The inhibitory effect of ciglitazone on leptin induced HSC proliferion was associated with the reversion of ERK activation. However, ciglitazone failed to reverse the phosphorylation of ERK in PDGF activated HSCs, and it seemed that its effect might be on downstream of ERK activation. In conclusion, HSCs were leptin receptor expressing cells, and ciglitazone, one of PPAR-g ligands could regulate the expression of leptin receptor mRNA.