Gamma-linolenic Acid Inhibits Hepatic PAI-1 Expression by Inhibiting P38 MAPK-dependent Activator Protein and Mitochondria-mediated Apoptosis Pathway
Authors
Affiliations
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.
Cai Q, Yu S, Zhao J, Ma D, Jiang L, Zhang X J Oncol. 2022; 2022:5989419.
PMID: 35774357 PMC: 9239767. DOI: 10.1155/2022/5989419.
Park J, Jang K, An H, Kim J, Gwon M, Gu H Molecules. 2018; 23(9).
PMID: 30177595 PMC: 6225234. DOI: 10.3390/molecules23092236.
Park J, Seo Y, Jang J, Jeong C, Lee S, Park B J Neuroinflammation. 2017; 14(1):240.
PMID: 29228978 PMC: 5725763. DOI: 10.1186/s12974-017-1009-0.
Park J, Park B, Park K Toxins (Basel). 2017; 9(4).
PMID: 28406452 PMC: 5408212. DOI: 10.3390/toxins9040138.