Resveratrol Improves Recovery and Survival of Diet-Induced Obese Mice Undergoing Extended Major (80%) Hepatectomy
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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.
DIO mice were fed resveratrol or carrier control by gavage. EGFR expression and the response to major (80%) PH were examined.
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.
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.
KeywordsLiver regeneration Fatty liver Cytokines Hepatectomy Epidermal growth factor receptor Liver surgery
Epidermal growth factor
Mitogen-activated protein kinase
Proliferating cell nuclear antigen
Signal transducer and activator of transcription
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.).
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.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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