title: 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.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, China.
authors.forename: W
authors.initials: W
authors.lastname: Shan
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, China.
authors.forename: L
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, China.
authors.forename: W
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: G
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, China.
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, China.
authors.forename: X
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: X
authors.identifier: 0000000266542270
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, China.
authors.forename: J
authors.initials: J
authors.lastname: Yao
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D019308:Palmitic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000637:Transaminases / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D045784:Abietanes; D000975:Antioxidants; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; C560944:MIRN34 microRNA, rat; D035683:MicroRNAs; D020011:Protective Agents; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014280:Triglycerides; D019308:Palmitic Acid; D013482:Superoxide Dismutase; D000637:Transaminases; D053148:Caspase 3; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; C018381:salvin