Methyl ferulic acid attenuates liver fibrosis and hepatic stellate cell activation through the TGF-β1/Smad and NOX4/ROS pathways.

Abstract

Liver fibrosis is a pathological wound-healing response caused by chronic liver damage due to a virus, autoimmune disorder, or drugs. Hepatic stellate cells (HSCs) play an essential role in the pathogenesis of liver fibrosis. Methyl ferulic acid (MFA), a biologically active monomer, has a protective effect on liver injury. However, the effects and roles of MFA in liver fibrosis remain unknown. The purpose of the current study was to investigate the effect of MFA on hepatic fibrosis and the underlying mechanisms. Human hepatic stellate LX-2 cells were exposed to 5 μg/L TGF-β1 for 48 h to stimulate liver fibrosis in vitro. Using MTT, RT-PCR and Western blot analysis, we revealed that MFA significantly inhibited the proliferation of LX-2 cells as well as decreased the expressions of α-SMA and type I collagen in LX-2 cells. SD rats were fed with ethanol, and this combined with the intraperitoneal injection of CCl4 induced liver fibrosis in vivo. We found that the administration of MFA markedly decreased the levels of hyaluronic acid (HA), procollagen type III (PC-III), type IV collagen (CIV) and laminin (LN) in the serum, inhibited the expression of α-smooth muscle actin (α-SMA) as well as type I and type III collagen, and up-regulated the ratio of MMP-2/TIMP-1 in rats. The antifibrotic effects of MFA were also evaluated by H&E staining and Masson's trichrome staining. In addition, further studies suggested that this protection by MFA from liver fibrosis was possibly related to the inhibition of TGF-β1/Smad and NOX4/ROS signalling. In conclusion, our results demonstrate that MFA attenuated liver fibrosis and hepatic stellate cell activation by inhibiting the TGF-β1/Smad and NOX4/ROS signalling pathways.

• Authors: Qi Cheng, Chen Li, Cheng-Fang Yang, Yu-Juan Zhong, Dan Wu, Lin Shi, Li Chen, Yong-Wen Li, Li Li
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 299 Pg. 131-139 (Feb 01 2019) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 30543783 (Publication Type: Journal Article)
• Copyright: Copyright © 2018. Published by Elsevier B.V.

Chemical References

• ACTA2 protein, human
• Actins
• Collagen Type I
• Collagen Type III
• Coumaric Acids
• Laminin
• Reactive Oxygen Species
• Smad Proteins
• Transforming Growth Factor beta1
• Hyaluronic Acid
• ferulic acid
• NADPH Oxidase 4

Topics

• Actins (genetics, metabolism)
• Animals
• Collagen Type I (genetics, metabolism)
• Collagen Type III (genetics, metabolism)
• Coumaric Acids (pharmacology)
• Gene Expression Regulation (drug effects)
• Hepatic Stellate Cells (cytology, drug effects, metabolism)
• Humans
• Hyaluronic Acid (blood)
• Laminin (blood)
• Liver (metabolism, pathology)
• Liver Cirrhosis (chemically induced, drug therapy, pathology, veterinary)
• Male
• NADPH Oxidase 4 (metabolism)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Smad Proteins (metabolism)
• Transforming Growth Factor beta1 (metabolism, pharmacology)