Indole-3-propionic Acid-aggravated CCl_(4)-induced Liver Fibrosis via the TGF-β1/Smads Signaling Pathway

Background and Aims:The pathogenesis of liver fibrosis involves liver damage,inflammation,oxidative stress,and intestinal dysfunction.Indole-3-propionic acid(IPA)has been demonstrated to have antioxidant,anti-inflammatory and anticancer activities,and a role in maintaining gut homeostasis.The current study aimed to investigate the role of IPA in carbon tetrachloride(CCl4)-induced liver fibrosis and explore the underlying mechanisms.Methods:The liver fibrosis model was established in male C57BL/6 mice by intraperitoneal injection of CCl4 twice weekly.IPA intervention was made orally(20 mg/kg daily).The degree of liver injury and fibrosis were assessed by serum alanine aminotransferase(ALT),aspartate aminotransferase(AST),and histopathology.Enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction(qPCR)were used to detect the inflammatory cytokines.The malondialdehyde(MDA),glutathione,glutathione peroxidase,superoxide dismutase,and catalase were determined via commercial kits.Hepatocyte apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay.The expression of mRNA and protein was assayed by qPCR,Western blotting,or immunohistochemical staining.Results:After IPA treatment,the ALT and AST,apoptotic cells,and pro-inflammatory factor levels were enhanced significantly.Moreover,IPA intervention up-regulated the expression of collagen I,α-smooth muscle actin,tissue inhibitor of matrix metalloproteinase-1,matrix metalloproteinase-2,transforming growth factor-β1(TGF-β1),Smad3,and phosphorylated-Smad2/3.Additionally,IPA intervention did not affect the MDA level.Attractively,the administration of IPA remodeled the gut flora structure.Conclusions:IPA aggravated CCl_(4)-induced liver damage and fibrosis by activating HSCs via the TGF-β1/Smads signaling pathway.