Resveratrol prevents liver fibrosis via two possible pathways: Modulation of alpha fetoprotein transcriptional levels and normalization of protein kinase C responses

Abstract

Objective: Liver fibrosis is a global health problem that causes approximately 1.4 million deaths per year. It is associated with inflammation, oxidative stress, necrosis and ends with cirrhosis, liver cancer, or liver failure. Therefore, the present study was constructed to investigate the protective effect of resveratrol (RVT) on liver fibrosis, focusing on the possible involvement of alpha 1-fetoprotein and protein kinase C signaling.

Materials and methods: Rats received thioacetamide (TAA) (200 mg/kg, intraperitoneal) twice weekly, for 4 successive weeks to induce liver fibrosis. RVT (30 mg/kg, per os) and vehicle were administered orally for 1 month before and another month during TAA intoxication. Body weights and mortality rate were assessed during the experiment. Liver functions and protein concentration were determined in serum, while liver tissues were analyzed for oxidative and fibrotic biomarkers. Moreover, histological examinations were performed to liver biopsies.

Results: RVT prevented the debility of TAA; liver functions including alanine aminotransferase, aspartate aminotransferase, bilirubin, and albumin were also protected. RVT prevented TAA oxidative stress, and normal liver contents of malondialdehyde and reduced glutathione were markedly preserved. In addition, RVT abolished the stimulant effect of TAA to fibrosis markers and conserved normal liver contents of nuclear factor kappa B, hydroxyproline, and alpha fetoprotein. Histological examinations indicated normal liver architecture in RVT-administered rats as compared to their TAA-administered peers.

Conclusion: RVT was able to enhance liver functions, prevent oxidative stress, and eliminate liver fibrosis. Hence, the present data highlight the therapeutic potential of RVT as a protective agent against liver fibrosis.

Keywords: alpha 1-fetoprotein; liver fibrosis; protein kinase C signaling; rats; thioacetamide.

Figure 1

(a) The protective effect of resveratrol on rats' body weights in TAA-induced liver fibrosis model. Statistical analysis was carried out by two-way ANOVA followed by Tukey's test. Data expressed as mean ± standard error of the mean, n = 18. *Significant from normal group at respective time at P ≤ 0.05. @Significant from control group at respective time at P ≤ 0.05. Exact P ≤ 0.05 is mentioned; however, P < 0.001 are presented as P < 0.001. (b) Resveratrol decreased the percent of mortality in TAA-induced liver fibrosis rats. Numbers of rats were checked daily, and from which the mortality percent was calculated by using the formula (number of dead rats in a group/total number of rats in the same group) ×100. TAA = Thioacetamide, RVT=Resveratrol

Figure 2

The effect of resveratrol on alpha 1-fetoprotein in thioacetamide-induced liver fibrosis model in rats. Statistical analysis was carried out by one-way ANOVA followed by Tukey's test. Data expressed as mean ± standard error of the mean, n = 18. *Significant from normal group at respective time at P ≤ 0.05. @Significant from control group at respective time at P ≤ 0.05. Exact P ≤ 0.05 is mentioned; however, P < 0.001 are presented as P < 0.001. RVT = Resveratrol

Figure 3

Histological features of pretreatment of resveratrol on liver tissues of rats in TAA-induced liver fibrosis model. Sections were cut and stained with HE and MT. (a) Negative control group, HE stained. (b) Negative control group, MT stained. (c), TAA group, HE stained. (d) TAA group, MT stained. (e) RVT group, HE stained. (f) RVT group, MT stained. TAA = Thioacetamide, RVT = Resveratrol, HE = Hematoxylin and eosin, MT = Masson trichrome

Figure 4

This has been proposed by our group as a possible explanation for RVT effects against liver fibrosis. RVT is a lipophilic compound; it can readily cross the cell membrane and bind to intracellular components. It can also exert its action through binding to specific receptors. RVT act as a free radical scavenger; thus, it prevents the detrimental effect of ROS on hepatocytes. It may also bind to PKC domains and AFP enhancer region and returns them back to their normal activities. TAA = Thioacetamide, RVT = Resveratrol, ROS = Reactive oxygen species, GSH = reduced glutathione, ALT = Alanine aminotransferase, AST = aspartate aminotransferase, PKC = protein kinase C, AP-1 = Activator protein 1, MMP = Matrix metalloproteinase, AFP = Alpha 1-fetoprotein, ECM = Extracellular matrix component, NF-κB = Nuclear factor kappa B