Activation of the SIRT1/p66shc antiapoptosis pathway via carnosic acid-induced inhibition of miR-34a protects rats against nonalcoholic fatty liver disease.

Abstract

Recent studies have demonstrated that miR-34a expression is significantly upregulated and associated with apoptosis in nonalcoholic fatty liver disease (NAFLD). Carnosic acid (CA) is a novel antioxidant and a potential inhibitor of apoptosis in organ injury, including liver injury. This study aimed to investigate the signaling mechanisms underlying miR-34a expression and the antiapoptotic effect of CA in NAFLD. CA treatment significantly reduced the high-fat diet (HFD)-induced elevations in aminotransferase activity as well as in serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and malondialdehyde (MDA) levels but increased serum high-density lipoprotein cholesterol (HDL-C) and hepatic superoxide dismutase (SOD) levels. Moreover, CA treatment ameliorated the increase in cleaved caspase-3 caused by HFD exposure and completely reversed the HFD-induced decreases in manganese superoxide dismutase (MnSOD) and B-cell lymphoma-extra large expression. CA also counteracted the HFD- or palmitic acid (PA)-induced increases in caspase-3 and caspase-9 activity. Mechanistically, CA reversed the HFD- or PA-induced upregulation of miR-34a, which is the best-characterized regulator of SIRT1. Importantly, the decrease in miR-34a expression was closely associated with the activation of the SIRT1/p66shc pathway, which attenuates hepatocyte apoptosis in liver ischemia/reperfusion injury. A dual luciferase assay in L02 cells validated the modulation of SIRT1 by CA, which occurs at least partly via miR-34a. In addition, miR-34a overexpression was significantly counteracted by CA, which prevented the miR-34a-dependent repression of the SIRT1/p66shc pathway and apoptosis. Collectively, our results support a link between liver cell apoptosis and the miR-34a/SIRT1/p66shc pathway, which can be modulated by CA in NAFLD.

• Authors: W Shan, L Gao, W Zeng, Y Hu, G Wang, M Li, J Zhou, X Ma, X Tian, J Yao
• Journal: Cell death & disease (Cell Death Dis) Vol. 6 Pg. e1833 (Jul 23 2015) ISSN: 2041-4889 [Electronic] England
• PMID: 26203862 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Abietanes
• Antioxidants
• Lipoproteins, HDL
• Lipoproteins, LDL
• MIRN34 microRNA, rat
• MicroRNAs
• Protective Agents
• Shc Signaling Adaptor Proteins
• Shc1 protein, rat
• Src Homology 2 Domain-Containing, Transforming Protein 1
• Triglycerides
• Palmitic Acid
• Superoxide Dismutase
• Transaminases
• Caspase 3
• Sirt1 protein, rat
• Sirtuin 1
• salvin

Topics

• Abietanes (pharmacology)
• Animals
• Antioxidants (pharmacology)
• Apoptosis (drug effects, genetics)
• Caspase 3 (genetics, metabolism)
• Diet, High-Fat (adverse effects)
• Gene Expression Regulation
• Hepatocytes (drug effects, metabolism, pathology)
• Lipoproteins, HDL (blood)
• Lipoproteins, LDL (blood)
• Male
• MicroRNAs (genetics, metabolism)
• Non-alcoholic Fatty Liver Disease (drug therapy, etiology, genetics, metabolism)
• Palmitic Acid (antagonists & inhibitors, pharmacology)
• Protective Agents (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Shc Signaling Adaptor Proteins (genetics, metabolism)
• Signal Transduction
• Sirtuin 1 (genetics, metabolism)
• Src Homology 2 Domain-Containing, Transforming Protein 1
• Superoxide Dismutase (genetics, metabolism)
• Transaminases (genetics, metabolism)
• Triglycerides (blood)