Metformin inhibits mTOR–HIF‐1α axis and profibrogenic and inflammatory biomarkers in thioacetamide‐induced hepatic tissue alterations

Abstract

The potential inhibitory effect of the antidiabetic and anti‐inflammatory drug, metformin on thioacetamide (TAA)‐induced hepatotoxicity associated with the inhibition of mammalian target of rapamycin (mTOR)–hypoxia‐inducible factor‐1α (HIF‐1α) axis has not been investigated before. Therefore, we tested whether metformin can protect against liver injuries including fibrosis induced by TAA possibly via the downregulation of mTOR–HIF‐1α axis and profibrogenic and inflammatory biomarkers. Rats either injected with TAA (200 mg/kg; twice a week for 8 weeks) before being killed after 10 weeks (model group) or were pretreated with metformin (200 mg/kg) daily for 2 weeks before TAA injections and continued receiving both agents until the end of the experiment, at Week 10 (protective group). Using light and electron microscopy examinations, we observed in the model group substantial damage to the hepatocytes and liver tissue such as collagen deposition, infiltration of inflammatory cells, and degenerative cellular changes with ballooned mitochondria that were substantially ameliorated by metformin. Metformin also significantly ( p < 0.05) inhibited TAA‐induced HIF‐1α, mTOR, the profibrogenic biomarker α‐smooth muscle actin, tissue inhibitor of metalloproteinases‐1, tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), alanine aminotransferase (ALT) and aspartate aminotransferase in harvested liver homogenates and blood samples. In addition, a significant ( p < 0.01) positive correlation between hypoxia scoring (HIF‐1α) and the serum levels of TNF‐α ( r = 0.797), IL‐6 ( r = 0.859), and ALT ( r = 0.760) was observed. We conclude that metformin protects against TAA‐induced hepatic injuries in rats, which is associated with the inhibition of mTOR–HIF‐1α axis and profibrogenic and inflammatory biomarkers; thus, may offer therapeutic potential in humans.

Dendrobium officinale Polysaccharide Protected CCl4-Induced Liver Fibrosis Through Intestinal Homeostasis and the LPS-TLR4-NF-κB Signaling Pathway

“…HSC cells are the most activated cells in liver fibrosis and involve in collagen synthesis, and alpha-smooth muscle actin (α-SMA) is the sign of HSC cell activation (Chiu et al, 2014). Many small molecules are important triggers of liver fibrosis, such as tumor necrosis factoralpha (TNF-α), interleukin-10 (IL-10), and transforming growth factor-beta (TGF-β), which possess effective pro-inflammatory or anti-inflammatory effects (Seki and Brenner, 2015;Kim et al, 2016;Al-Hashem et al, 2019;Xu et al, 2019). Inflammation promotes the activation of HSC cells and aggravates liver fibrosis, ultimately leading to cirrhosis of the liver, which endangers human life (Mitra et al, 2014).…”

Suppression of Thioacetamide-Induced Hepatic Injury in Rats treatment with Resveratrol: Role of mammalian Target of Rapamycin (mTOR) Cell Signaling

“…Inflammation and necrosis of liver tissue also observed after one week following a single injection of TAA (Luo et al, 2015). On the other hand, chronic liver injury model induced by TAA injections twice a week for 6 to 10 weeks caused liver fibrosis and cirrhosis (Wallace et al, 2015;Al-Hashem et al, 2019).…”

Suppression of Hepatic Apoptosis Induced by Acetaminophen Using a Combination of Resveratrol and Quercetin: An Association of Oxidative Stress and Interleukin-11

“…Liver specimens were dissected out by midline laparotomy and immediately fixed in 10 % formol saline for 24 hours. Paraffin blocks were processed, sectioned in 5mm thickness and subjected to H&E staining to observe the morphological changes (Al-Hashem et al, 2019).…”