Deficiency of miR-208a Exacerbates CCl 4 -Induced Acute Liver Injury in Mice by Activating Cell Death Pathways

• Published in: Hepatology communications Vol. 4; no. 10; pp. 1487 - 1501
• Main Authors: Bala, Shashi, Calenda, Charles D, Catalano, Donna, Babuta, Mrigya, Kodys, Karen, Nasser, Imad A, Vidal, Barbara, Szabo, Gyongyi
• Format: Journal Article
• Language: English
• Published: United States Wolters Kluwer Health Medical Research, Lippincott Williams & Wilkins 01-10-2020
• Subjects: Adapter proteins; Antibodies; Antigens; Apoptosis; Cancer; Cell death; Deoxyribonucleic acid; DNA; DNA damage; Enzymes; Extracellular vesicles; Inflammation; Kinases; Liver; Lymphoma; MicroRNAs; Nanoparticles; Oxidative stress; Permeability; Polymerase chain reaction; Roles; Tumor necrosis factor-TNF; Germany
• ISSN: 2471-254X
• DOI: 10.1002/hep4.1540

Acute liver injury (ALI) is associated with multiple cellular events such as necrosis, apoptosis, oxidative stress and inflammation, which can lead to liver failure. In this study, we demonstrate a new role of microRNA (miR)-208a in ALI. ALI was induced in wild-type (WT) and miR-208a knockout (KO) mice by CCl
administration. Increased alanine aminotransferase and decreased hepatic miR-208a levels were found in WT mice after acute CCl
treatment. Histopathological evaluations revealed increased necrosis and decreased inflammation in miR-208a KO compared with WT mice after CCl
treatment. CCl
treatment induced a higher alanine aminotransferase elevation and increased numbers of circulating extracellular vesicles (exosomes and microvesicles) in miR-208a KO compared with WT mice. We found increased CCl
-induced nuclear factor kappa B activation and tumor necrosis factor-α induction and decreased monocyte chemoattractant protein 1 levels in miR-208a KO compared with WT mice. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay indicated aggravated hepatic apoptosis and necrosis in CCl
treated miR-208a KO compared with WT mice. CCl
treatment induced a greater increase in cleaved caspase-8, p18, and caspase-3 in miR-208a KO compared with WT mice. p53 is involved in various cell death pathways, including necrosis and apoptosis. Our
analysis revealed p53 as a predicted miR-208a target, and we found enhanced p53 and cyclophilin D protein expressions in miR-208a KO mice after CCl
treatment. Increased liver injury in miR-208a KO mice was further associated with increased Bax (B cell lymphoma 2-associated X protein) and p21 expression. Our
results indicated a role of miR-208a in cell death. We found that CCl
-induced cytotoxicity was partially rescued by miR-208a overexpression in RAW macrophages. Altogether, our results revealed a role of miR-208a in ALI in mice and suggest a role for miR-208a in regulating cell death.