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

• Published in: Journal of cellular physiology Vol. 234; no. 6; pp. 9328 - 9337
• Main Authors: Al‐Hashem, Fahaid, Al‐Humayed, Suliman, Amin, Shaimaa N., Kamar, Samaa S., Mansy, Soheir S., Hassan, Sarah, Abdel‐Salam, Lubna O., Ellatif, Mohamed Abd, Alfaifi, Mohammed, Haidara, Mohamed A., Al‐Ani, Bahjat
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-06-2019
• Subjects: Actin; Alanine; Alanine transaminase; Animals; Antidiabetics; Aspartate aminotransferase; Biomarkers; Biomarkers - metabolism; Chronic Disease; Collagen; Correlation analysis; Diabetes mellitus; Electron microscopy; Fibrosis; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - pathology; Hepatocytes - ultrastructure; Hepatotoxicity; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Infiltration; Inflammation; Inflammation - pathology; Injuries; Interleukins; Liver; Liver - drug effects; Liver - injuries; Liver - metabolism; Liver - pathology; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; liver fibrosis; Male; Metastases; Metformin; Metformin - pharmacology; Mitochondria; mTOR–HIF‐1α axis; Muscles; Protective Agents - pharmacology; Rapamycin; rat model; Rats; Rodents; Serum levels; Signal Transduction - drug effects; Smooth muscle; Thioacetamide; Tissue inhibitor of metalloproteinases; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tumor necrosis factor; Tumor necrosis factor-TNF; thioacetamide; metformin; liver fibrosis; rat model; mTOR-HIF-1α axis; inflammation
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.27616

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.
Upregulation of hypoxia‐inducible factor‐1α (HIF‐1α), mammalian target of rapamycin (mTOR), and the profibrogenic biomarker α‐smooth muscle actin (α‐SMA) are known to promote liver fibrosis. The potential inhibitory effect of the antidiabetic and anti‐inflammatory drug, metformin on thioacetamide (TAA)‐induced hepatotoxicity associated with the inhibition of mTOR–HIF‐1α axis has not been investigated before. Therefore, we investigated the above problem in a rat model of the disease and found 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.