Research Paper Volume 12, Issue 3 pp 2049—2069
Targeting of miR-96-5p by catalpol ameliorates oxidative stress and hepatic steatosis in LDLr-/- mice via p66shc/cytochrome C cascade
- 1 Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China
received: October 7, 2019 ; accepted: January 2, 2020 ; published: February 5, 2020 ;https://doi.org/10.18632/aging.102721
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Copyright © 2020 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Hepatic steatosis and oxidative stress are considered to be the sequential steps in the development of non-alcoholic fatty liver disease (NAFLD). We previously found that catalpol, an iridoid glucoside extracted from the root of Romania glutinosa L, protected against diabetes-induced hepatic oxidative stress. Here, we found that the increased expression of p66shc was observed in NAFLD models and catalpol could inhibit p66shc expression to ameliorate NAFLD effectively. However, the underlying mechanisms remained unknown. The aim of the present study was to investigate the p66shc-targeting miRNAs in regulating oxidative stress and hepatic steatosis, also the mechanisms of catalpol inhibiting NAFLD. We found that the effects of catalpol inhibiting hepatic oxidative stress and steasis are dependent on inhibiting P66Shc expression. In addition, miR-96-5p was able to suppress p66shc/cytochrome C cascade via targeting p66shc mRNA 3’UTR, and catalpol could lead to suppression of NAFLD via upregulating miR-96-5p level. Thus, catalpol was effective in ameliorating NAFLD, and miR-96-5p/p66shc/cytochrome C cascade might be a potential target.
NAFLD: non-alcoholic fatty liver disease; LDLr-/-: Low density lipoprotein receptor knockout; PA: palmitic acid; oxLDL: oxidized low density lipoprotein; NASH: steatohepatitis; ROS: reactive oxygen species; ATP: adenosine triphosphate; mtDNA: mitochondrial deoxyribonucleic acid; TC: total cholesterol; TG: triglyceride; ALT: alanine aminotransferase; AST: aspartate aminotransferase; SOD: superoxide dismutase; MDA malondialdehyde; CAT: catalase; HFD: high fat diet; H2DCFDA: 2′, 7′- dichlorodihydrofluorescein diacetate; FACS: Fluorescent Activated Cell Sorting; Ago-2: Argonaute-2; RT-PCR: reverse transcription polymerase chain reaction; PVDF: polyvinylidene difluoride; TUNEL: terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling; SNK: student-newman-keuls.