Prolyl oligopeptidase attenuates hepatic stellate cell activation through induction of Smad7 and PPAR-γ

Abstract

Abstract. Prolyl oligopeptidase (POP) is a serine endopeptidase widely distributed in vivo with high activity in the liver. However, its biological functions in the liver have remained largely elusive. A previous study by our group has shown that POP produced N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) and thereby exerted an anti-fibrogenic effect on hepatic stellate cells (HSCs) in vitro. It was therefore hypothesized that POP may affect the activation state of HSCs and has an important role in liver fibrosis. The HSC-T6 immortalized rat liver stellate cell line was treated with the POP inhibitor S17092 or transfected with recombinant lentivirus to overexpress POP. Cell proliferation and apoptosis were determined using a Cell Counting Kit-8 and flow cytometry, respectively. The activation status of HSCs was determined by examination of the expression of α-smooth muscle actin (α-SMA), collagen I, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor (TGF)-β-Smad signaling and peroxisome proliferator activated receptor-γ (PPAR-γ). Inhibition by S17092 decreased, whereas lentiviral expression increased the activity of POP and cell proliferation, while neither of the treatments affected cell apoptosis. Of note, S17092 significantly increased, whereas POP overexpression decreased the expression of α-SMA and MCP-1 without affecting the expression of collagen I and TGF-β1. Furthermore, S17092 caused a reduction, whereas POP overexpression caused an upregulation of Smad7 protein and PPAR-γ, but not phosphorylated-Smad2/3 expression. In conclusion, POP attenuated the activation of HSCs through inhibition of TGF-β signaling and induction of PPAR-γ, which may have therapeutic potential in liver fibrosis.

Prolyl oligopeptidase regulates progesterone secretion via the ERK signaling pathway in murine luteal cells

“…In pancreatic cancer cells, POP inhibition or degradation was shown to inhibit the PI3K/AKT pathway by preventing insulin receptor substrate 1 (IrS1) degradation (Duan et al, ). In hepatic stellate cells, POP reduced signaling by transforming growth factor β (TGFB) superfamily members via induction of the inhibitory molecules Smad 7 and PPAR‐γ (Zhou et al, ). POP has been shown to regulate inositol (1,4,5) trisphosphate (IP3) production via its effects on multiple inositol polyphosphate phosphatases (MINPP), which are associated with clinical depression (Williams & Harwood, ).…”

Platyconic Acid A, Platycodi Radix-Derived Saponin, Suppresses TGF-β1-Induced Activation of Hepatic Stellate Cells via Blocking SMAD and Activating the PPARγ Signaling Pathway

“…PPARγ is a key molecular switch that regulates HSCs activation and phenotypic alterations to maintain a quiescent HSCs phase that includes the prevention of the TGF-β1 signal, suppression of α-SMA, loss of type I collagen, and reduction of cell proliferation [11,31]. Therefore, PPARγ plays an important role in reducing and preventing liver fibrosis via inhibition of HSCs activation.…”

“…PPARγ blocks the TGF-β pathway to suppress myofibroblast transdifferentiation from fibroblasts. Finally, PPARγ inhibits TGF-β-induced downstream signal transduction and hepatic fibrogenesis [11]. Recent studies have reported that PPARγ is activated by natural and pharmacological agents.…”

Interactions between TGF-β1, canonical WNT/β-catenin pathway and PPAR γ in radiation-induced fibrosis

“…Rosiglitazone, a PPAR γ agonist, could decrease fibrosis by stimulating Smad7, an inhibitor of TGF/Smad signaling pathway [ 325 ]. In liver fibrosis, overexpression of prolyl oligopeptidase (POP) by S17092 (a POP inhibitor) leads to activate Smad7 protein and PPAR γ and then inactivates TGF-β signaling [ 326 ].…”