PMID- 29693586 OWN - NLM STAT- MEDLINE DCOM- 20180924 LR - 20181114 IS - 2072-6643 (Electronic) IS - 2072-6643 (Linking) VI - 10 IP - 5 DP - 2018 Apr 25 TI - Ellagic Acid Alleviates Hepatic Oxidative Stress and Insulin Resistance in Diabetic Female Rats. LID - 10.3390/nu10050531 [doi] LID - 531 AB - Non-alcoholic fatty liver disease (NAFLD) affects more than 70% of patients with type 2 diabetes mellitus (T2DM) and has become one of the most common metabolic liver diseases worldwide. To date, treatments specifically targeting NAFLD do not exist. Oxidative stress and insulin resistance have been implicated in the pathogenesis of NAFLD in diabetes. Accordingly, the goal of this present study was to determine whether Ellagic acid (EA), a natural antioxidant polyphenol found in berries and nuts, mitigates hepatic oxidative stress and insulin resistance in T2DM rats, and thus alleviates NAFLD. Using adult female Goto Kakizaki (GK) rats, a non-obese and spontaneous model of T2DM, we found that EA treatment significantly lowered fasting blood glucose and reduced insulin resistance, as shown by a 21.8% reduction in the homeostasis model assessment index of insulin resistance (HOMA-IR), while triglyceride and total cholesterol levels remained unchanged. Increased hepatic lipid accumulation and oxidative stress present in diabetic GK rats was markedly reduced with EA treatment. This effect was associated with a downregulation of the NADPH oxidase subunit, p47-phox, and overexpression of NF-E2-related factor-2 (NRF2). Moreover, EA was able to decrease the hepatic expression of hypoxia-inducible factor (HIF-α), a transcription factor linked to hypoxia and hepatic steatosis. We further showed that EA treatment activated an insulin signaling pathway in the liver, as evidenced by increased levels of phosphorylated Akt (Ser 473). In conclusion, our results demonstrate that EA diminishes blood glucose levels and potently suppress NAFLD in diabetic rats via mechanisms that involve reductions in p47-phox and HIF-α, upregulation of NRF2 and enhancement of the Akt signaling pathway in the liver. Together, these results reveal that EA improves hepatic insulin sensitivity and lipid metabolism as a result of its antioxidant effects. This implies an anti-diabetic effect of EA with beneficial effects for the treatment of hepatic complications in T2DM. FAU - Polce, Simran Alexandria AU - Polce SA AD - Department of Life Sciences, College of Arts and Sciences, New York Institute of Technology, Old Westbury, NY 11568, USA. spolce@nyit.edu. FAU - Burke, Cameron AU - Burke C AD - Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY 11568, USA. cburke08@nyit.edu. FAU - Franca, Lucas Martins AU - Franca LM AUID- ORCID: 0000-0002-4412-1539 AD - Laboratory of Experimental Physiology, Department of Physiological Sciences, Federal University of Maranhao, Sao Luis, MA 65080-805, Brazil. lucas.mf@ufma.br. FAU - Kramer, Benjamin AU - Kramer B AD - Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY 11568, USA. bkramer@nyit.edu. FAU - de Andrade Paes, Antonio Marcus AU - de Andrade Paes AM AUID- ORCID: 0000-0002-4412-1539 AD - Laboratory of Experimental Physiology, Department of Physiological Sciences, Federal University of Maranhao, Sao Luis, MA 65080-805, Brazil. antonio.marcus@ufma.br. FAU - Carrillo-Sepulveda, Maria Alicia AU - Carrillo-Sepulveda MA AD - Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY 11568, USA. mcarrill@nyit.edu. LA - eng PT - Journal Article DEP - 20180425 PL - Switzerland TA - Nutrients JT - Nutrients JID - 101521595 RN - 0 (Antioxidants) RN - 0 (Biomarkers) RN - 0 (Blood Glucose) RN - 0 (HIF1A protein, human) RN - 0 (Hypoglycemic Agents) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Insulin) RN - 0 (Lipids) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Nfe2l2 protein, rat) RN - 19YRN3ZS9P (Ellagic Acid) RN - EC 1.6.3.- (NADPH Oxidases) RN - EC 1.6.3.1 (neutrophil cytosolic factor 1) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Animals MH - Antioxidants/*pharmacology MH - Biomarkers/blood MH - Blood Glucose/*drug effects/metabolism MH - Diabetes Mellitus, Type 2/blood/*drug therapy/physiopathology MH - Disease Models, Animal MH - Ellagic Acid/*pharmacology MH - Female MH - Hypoglycemic Agents/*pharmacology MH - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism MH - Insulin/blood MH - *Insulin Resistance MH - Lipids/blood MH - Liver/*drug effects/metabolism MH - NADPH Oxidases/metabolism MH - NF-E2-Related Factor 2/metabolism MH - Non-alcoholic Fatty Liver Disease/metabolism/prevention & control MH - Oxidative Stress/*drug effects MH - Phosphorylation MH - Proto-Oncogene Proteins c-akt/metabolism MH - Rats MH - Time Factors PMC - PMC5986411 OTO - NOTNLM OT - Ellagic Acid OT - Goto-kakizaki (GK) rats OT - HIF-alpha OT - NRF2 OT - Type II Diabetes Mellitus (T2DM) OT - antioxidant OT - hepatic steatosis OT - insulin resistance OT - oxidative stress OT - p47-phox COIS- The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. EDAT- 2018/04/26 06:00 MHDA- 2018/09/25 06:00 PMCR- 2018/05/01 CRDT- 2018/04/26 06:00 PHST- 2018/04/04 00:00 [received] PHST- 2018/04/18 00:00 [revised] PHST- 2018/04/23 00:00 [accepted] PHST- 2018/04/26 06:00 [entrez] PHST- 2018/04/26 06:00 [pubmed] PHST- 2018/09/25 06:00 [medline] PHST- 2018/05/01 00:00 [pmc-release] AID - nu10050531 [pii] AID - nutrients-10-00531 [pii] AID - 10.3390/nu10050531 [doi] PST - epublish SO - Nutrients. 2018 Apr 25;10(5):531. doi: 10.3390/nu10050531.