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Metformin inhibits mTOR–HIF-1α axis and profibrogenic and inflammatory biomarkers in thioacetamide-induced hepatic tissue alterations |
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| Authors: | Fahaid Al-Hashem Suliman Al-Humayed Shaimaa N Amin Samaa S Kamar Soheir S Mansy Sarah Hassan Lubna O Abdel-Salam Mohamed Abd Ellatif Mohammed Alfaifi Mohamed A Haidara Bahjat Al-Ani |
| Institution: | 1. Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia;2. Department of Medicine, College of Medicine, King Khalid University, Abha, Saudi Arabia;3. Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt;4. Department of Medical Histology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt;5. Electron Microscopy Research Department, Theodor Bilharz Research Institute, Cairo, Egypt;6. Department of Pathology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt;7. Department of Biochemistry, College of Medicine, King Khalid University, Abha, Saudi Arabia
Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura, Egypt;8. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia;9. Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt Mohamed A. Haidara and Bahjat Al-Ani equally contributed to this work. |
| 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. |
| Keywords: | inflammation liver fibrosis metformin mTOR–HIF-1α axis rat model thioacetamide |