Pigment Epithelium-Derived Factor Is an Intrinsic Antifibrosis Factor Targeting Hepatic Stellate Cells

Abstract

The liver is the major site of pigment epithelium-derived factor (PEDF) synthesis. Recent evidence suggests a protective role of PEDF in liver cirrhosis. In the present study, immunohistochemical analyses revealed lower PEDF levels in liver tissues of patients with cirrhosis and in animals with chemically induced liver fibrosis. Delivery of the PEDF gene into liver cells produced local PEDF synthesis and ameliorated liver fibrosis in animals treated with either carbon tetrachloride or thioacetamide. In addition, suppression of peroxisome proliferator-activated receptor gamma expression, as well as nuclear translocation of nuclear factorkappa B was found in hepatic stellate cells (HSCs) from fibrotic livers, and both changes were reversed by PEDF gene delivery. In culture-activated HSCs, PEDF, through the induction of peroxisome proliferator-activated receptor gamma, reduced the activity of nuclear factorkappa B and prevented the nuclear localization of JunD. In conclusion, our observations that PEDF levels are reduced during liver cirrhosis and that PEDF gene delivery ameliorates cirrhosis suggest that PEDF is an intrinsic protector against liver cirrhosis. Direct inactivation of HSCs and the induction of apoptosis of activated HSCs may be two of the mechanisms by which PEDF suppresses liver cirrhosis. (Am J Pathol

Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1

“…20 However, in pancreatitis responses, the early fibrosis seen in PEDF-null mice suggests that PEDF serves as a counterregulatory mechanism in pancreatitis. This function is also consistent with recently published data 8,10,18,19 on PEDF's antifibrotic role in the kidney, liver, heart, and eye. PEDF overexpression in a transgenic mouse model ameliorated the increase in TGF-␤1 and inflammatory markers in an eye injury model associated with neovascularization and fibrosis.…”

“…5,9,10 Similarly, the pancreas of PEDF-null mice displayed baseline enhanced ␣-smooth muscle actin expression, consistent with PSC activation (Figure 2A). The pancreatic gene expression profile of PEDF-null mice mirrored these findings.…”

“…8,10,18,19 Pancreatic PEDF expression by mRNA and tissue labeling increased with pancreatitis responses. Ethanol feeding accentuated PEDF labeling, which was most robust in regions of stromal expansion and ductular proliferation.…”

“…9 Decreased PEDF levels also occurred in cirrhotic human and rodent livers compared with normal specimens, suggesting that its loss is permissive for liver fibrosis. 10 Moreover, PEDF delivery in two models of cirrhosis markedly reduced stellate cell activation and liver fibrosis through induction of antifibrogenic transcription factors, such as peroxisome proliferator-activated receptor-␥, and suppression of pro-inflammatory cytokines, such as monocyte chemotactic protein-1. 10 The antifibrogenic properties of PEDF have also been demonstrated in other organs, including the kidney, heart, and eye.…”

“…10 Moreover, PEDF delivery in two models of cirrhosis markedly reduced stellate cell activation and liver fibrosis through induction of antifibrogenic transcription factors, such as peroxisome proliferator-activated receptor-␥, and suppression of pro-inflammatory cytokines, such as monocyte chemotactic protein-1. 10 The antifibrogenic properties of PEDF have also been demonstrated in other organs, including the kidney, heart, and eye. 7,8,18,19 PEDF delivery ameliorated kidney fibrosis and proteinuria by suppressing transforming growth factor (TGF)-␤1 expression in diabetic rats.…”