Gamma-linolenic acid inhibits hepatic PAI-1 expression by inhibiting p38 MAPK-dependent activator protein and mitochondria-mediated apoptosis pathway

Apoptosis. 2015 Mar;20(3):336-47. doi: 10.1007/s10495-014-1077-x.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Line
  • Fibrosis
  • Gene Expression Regulation
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Inflammation / prevention & control
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism
  • Promoter Regions, Genetic
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Serpin E2 / antagonists & inhibitors*
  • Serpin E2 / genetics
  • Serpin E2 / metabolism
  • Signal Transduction
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism
  • Transforming Growth Factor beta1 / antagonists & inhibitors*
  • Transforming Growth Factor beta1 / pharmacology
  • gamma-Linolenic Acid / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Anti-Inflammatory Agents, Non-Steroidal
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Serpin E2
  • Serpine2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Smad4 Protein
  • Smad4 protein, mouse
  • Transforming Growth Factor beta1
  • gamma-Linolenic Acid
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • p38 Mitogen-Activated Protein Kinases