Ferulic acid attenuates liver fibrosis and hepatic stellate cell activation via inhibition of TGF-β/Smad signaling pathway

Abstract

PurposeLiver fibrosis is a worldwide health issue. Development of effective new drugs for treatment of this disease is of great importance. This study investigated the therapeutic effects of ferulic acid on liver fibrosis in vitro and in vivo.Materials and methodsHuman hepatic stellate cell line (HSC) LX-2 was used for in vitro assays. Transforming growth factor β1 (TGF-β1) was used to induce hepatic fibrosis in LX-2 cells. Western blot was used to detect protein levels of collagen I, fibronectin, α-smooth muscle actin (SMA), p-Smad2, p-Smad3, p-p38, and p-JNK. Gene expression was measured by RT-qPCR. Fluorescence staining was used to determine localization of Smad4. CCl4-induced hepatic fibrosis in SD rats was used as an in vivo model. Histological features were detected by hematoxylin and eosin staining. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hexadecenoic acid (HA), and hydroxyproline (Hyp) were measured by ELISA.ResultsTGF-β1 treatment significantly increased levels of collagen I, fibronectin, α-SMA, p-Smad2, p-Smad3, and Smad4 in LX-2 cells. Ferulic acid improved TGF-β1-induced hepatic fibrosis via regulation of the TGF-β1/Smad pathway. Consistent with in vitro data, CCl4 caused severe hepatic fibrosis in SD rats, as determined by ALT, AST, HA, and Hyp upregulation. Protein levels of p-Smad2 and p-Smad3 in liver tissues were significantly increased following treatment with CCl4. All CCL4-induced changes were markedly attenuated by ferulic acid treatment.ConclusionFerulic acid potently improved hepatic fibrosis via inhibition of the TGF-β1/Smad pathway in vitro and in vivo. These findings provided evidence for potential use of ferulic acid to treat or prevent liver fibrosis.

Prior Toxoplasma Gondii Infection Ameliorates Liver Fibrosis Induced by Schistosoma Japonicum through Inhibiting Th2 Response and Improving Balance of Intestinal Flora in Mice

“…Heat shock protein 47 (HSP47) is the molecular chaperone required for normal, synthesis and secretion of procollagen [32]. Hepatic hydroxyproline (HYP) is a signature amino acid for fibrillar collagens [33]. Consistent with the above findings, we found both serum and mRNA levels in liver tissues of HYP and HSP47 were increased in mono-infected mice as compared with control group, but could be significantly reversed by co-infection ( Figure 2H,J).…”

Ferulic Acid Alleviates Lipotoxicity-induced Hepatocellular Death Through SIRT1 Activating-regulated Autophagy Pathway, and Independently of AMPK and Akt in AML-12 Hepatocytes

“…FA acts as antioxidant due to its scavenging on radicals, instead of the formation of phenoxyl radicals, as well as inhibition of reactive oxygen species (ROS) generation through donation of a hydrogen atom. Previous studies showed that FA improved thioacetamide-and CCl4-induced hepatic brosis [25,26] and diosbulbin B-, cadmium-, and streptozotocin-induced liver damage [27][28][29]. FA supplementation signi cantly improved hepatic lipids metabolic disorder and decreased liver injury in high-fat diet-induced obese mice [30,31].…”

Ferulic acid alleviates lipotoxicity-induced hepatocellular death through the SIRT1-regulated autophagy pathway and independently of AMPK and Akt in AML-12 hepatocytes

“…FA acts as an antioxidant due to its scavenging of radicals, rather than the formation of phenoxyl radicals, as well as its inhibition of reactive oxygen species (ROS) generation through donation of a hydrogen atom. Previous studies showed that FA improved thioacetamide- and CCl4-induced hepatic fibrosis [ 25 , 26 ] and diosbulbin B-, cadmium-, and streptozotocin-induced liver damage [ 27 – 29 ]. FA supplementation significantly improved hepatic lipid metabolism disorder and decreased liver injury in high-fat-diet-induced obese mice [ 30 , 31 ].…”