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Resveratrol Improves Recovery and Survival of Diet-Induced Obese Mice Undergoing Extended Major (80%) Hepatectomy

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Abstract

Introduction

Loss of hepatic epidermal growth factor receptor (EGFR) expression is a cause for the increased perioperative risk for complications and death in patients with obesity and fatty liver undergoing liver resection. Herein, we set out to identify agents that might increase EGFR expression and improve recovery for patients with fatty liver undergoing resection. Using the diet-induced obese (DIO) mouse model of fatty liver, we examined resveratrol as a therapy to induce EGFR expression and improve outcomes following 80% partial hepatectomy (PH) in a murine model.

Methods

DIO mice were fed resveratrol or carrier control by gavage. EGFR expression and the response to major (80%) PH were examined.

Results

Based on an Illumina analysis, resveratrol was identified as increasing EGFR gene expression in A549 cells. Resveratrol was observed to also increase EGFR protein expression in A549 cells. DIO mice fed resveratrol by gavage (75 mg/kg) demonstrated an increased EGFR expression without the identified hepatic toxicity. Resveratrol and control mice subjected to 80% PH, a model of high mortality hepatectomy in DIO mice, demonstrated macroscopically decreased fatty liver and fewer liver hemorrhagic petechiae. Resveratrol pretreatment ameliorated liver injury and accelerated regeneration of the hepatic remnant after 80% PH including decreasing serum ALT and bilirubin, while increasing hepatic PCNA expression. Resveratrol increased induction of p-STAT3 and p-AKT after 80% hepatectomy. Resveratrol pretreatment significantly improved survival rates in DIO mice undergoing extended 80% PH.

Conclusions

Oral resveratrol restores EGFR expression in fatty liver. Resveratrol may be a promising protective agent in instances where extensive hepatic resection of fatty liver is required.

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Abbreviations

EGF:

Epidermal growth factor

MAPK/ERK:

Mitogen-activated protein kinase

min:

Minutes

PCNA:

Proliferating cell nuclear antigen

STAT:

Signal transducer and activator of transcription

DIO:

Diet-induced obese

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Acknowledgments

This work was supported by the Lilly Endowment, Inc. Physician Scientist Initiative and National Institutes of Health Grants GM6360301 (L.G.K.), CA122596 and GM092758 (T.A.Z.).

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Author notes

  1. Xiaoling Jin and Teresa A. Zimmers have contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Indiana University School of Medicine, EH 511 SGEN, Indianapolis, IN, 46202, USA

    Teresa A. Zimmers & Leonidas G. Koniaris

  2. Department of Surgery, Thomas Jefferson University School of Medicine, Philadelphia, PA, USA

    Xiaoling Jin & Zongxiu Zhang

Authors
  1. Xiaoling Jin
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  2. Teresa A. Zimmers
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  3. Zongxiu Zhang
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  4. Leonidas G. Koniaris
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Contributions

Jin, Zimmers, and Koniaris were involved in the concept and design; Jin, Zhang, and Zimmers conducted the experiments; Jin, Zimmers, Zhang, and Koniaris interpreted the data; Jin, Koniaris, and Zimmers drafted the manuscript; Jin, Zimmers, Zhang, and Koniaris were involved in critical revisions.

Corresponding author

Correspondence to Leonidas G. Koniaris.

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The authors declare that they have no conflict of interest.

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Jin, X., Zimmers, T.A., Zhang, Z. et al. Resveratrol Improves Recovery and Survival of Diet-Induced Obese Mice Undergoing Extended Major (80%) Hepatectomy. Dig Dis Sci 64, 93–101 (2019). https://doi.org/10.1007/s10620-018-5312-0

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  • DOI: https://doi.org/10.1007/s10620-018-5312-0

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