Abstract
Fibrosis is induced by the excessive and abnormal deposition of extracellular matrix (ECM) with various growth factors in tissues. Transforming growth factor beta 1 (TGF-β1), plays a role in inducing apoptosis, modulates fibrosis, and ECM accumulation. Plasminogen activator inhibitor 1 (PAI-1) plays an important role in the development hepatic fibrosis. The overexpression of PAI-1 induces ECM accumulation, the main hallmark of chronic liver diseases. Death of hepatocytes is a characteristic feature of chronic liver disease due to various causes. The TGF-β1-mediated apoptotic pathway is regarded as a promising therapeutic target in hepatic fibrosis. Gamma-linolenic acid (GLA) is of special interest as it possesses anti-fibrosis, anti-inflammatory, and anti-cancer properties. However, the precise mechanism for GLA in chronic liver disease is not still clear. The aim of the present study was to determine whether GLA prevents hepatic PAI-1 expression and apoptosis through the inhibition of TGF-β1-mediated molecular mediators. GLA attenuated TGF-β1-stimulated PAI-1 expression, and inhibited PAI-1 promoter activity in AML12 cells. This effect was mediated by Smad3/4, the p38 pathways. We also found that GLA suppressed TGF-β1-induced apoptotic activation of the Bcl-2 family and caspase family of proteins, which resulted in the inhibition of poly-ADP-ribose polymerase 1 cleavage. GLA ameliorates the pro-fibrotic and pro-apoptotic effects of TGF-β1 in hepatocytes, suggesting GLA exerts a protective effect on hepatocytes and has a therapeutic potential for the treatment of chronic liver disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Apoptosis / drug effects
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Apoptosis / genetics
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Cell Line
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Fibrosis
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Gene Expression Regulation
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Hepatocytes / drug effects*
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Hepatocytes / metabolism
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Hepatocytes / pathology
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Inflammation / genetics
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Inflammation / metabolism
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Inflammation / pathology
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Inflammation / prevention & control
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Mice
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Mitochondria / drug effects*
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Mitochondria / metabolism
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerase Inhibitors
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Poly(ADP-ribose) Polymerases / genetics
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Poly(ADP-ribose) Polymerases / metabolism
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Promoter Regions, Genetic
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Protein Binding / drug effects
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Serpin E2 / antagonists & inhibitors*
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Serpin E2 / genetics
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Serpin E2 / metabolism
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Signal Transduction
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Smad3 Protein / genetics
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Smad3 Protein / metabolism
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Smad4 Protein / genetics
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Smad4 Protein / metabolism
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Transforming Growth Factor beta1 / antagonists & inhibitors*
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Transforming Growth Factor beta1 / pharmacology
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gamma-Linolenic Acid / pharmacology*
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Poly(ADP-ribose) Polymerase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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Serpin E2
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Serpine2 protein, mouse
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Smad3 Protein
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Smad3 protein, mouse
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Smad4 Protein
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Smad4 protein, mouse
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Transforming Growth Factor beta1
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gamma-Linolenic Acid
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Parp1 protein, mouse
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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p38 Mitogen-Activated Protein Kinases