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Am J Physiol Endocrinol Metab. 2017 Oct 1;313(4):E440-E449. doi: 10.1152/ajpendo.00032.2017. Epub 2017 Jun 27.

Epidermal growth factor receptor restoration rescues the fatty liver regeneration in mice.

Author information

1
Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
2
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana.
3
Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.
4
Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
5
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
6
Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana; lkoniari@iu.edu.

Abstract

Hepatic steatosis is a common histological finding in obese patients. Even mild steatosis is associated with delayed hepatic regeneration and poor outcomes following liver resection or transplantation. We sought to identify and target molecular pathways that mediate this dysfunction. Lean mice and mice made obese through feeding of a high-fat, hypercaloric diet underwent 70 or 80% hepatectomy. After 70% resection, obese mice demonstrated 100% survival but experienced increased liver injury, reduced energy stores, reduced mitoses, increased necroapoptosis, and delayed recovery of liver mass. Increasing liver resection to 80% was associated with mortality of 40% in lean and 80% in obese mice (P < 0.05). Gene expression profiling showed decreased epidermal growth factor receptor (EGFR) in fatty liver. Meta-analysis of expression studies in mice, rats, and patients also demonstrated reduction of EGFR in fatty liver. In mice, both EGFR and phosphorylated EGFR decreased with increasing percent body fat. Hydrodynamic transfection of EGFR plasmids in mice corrected fatty liver regeneration, reducing liver injury, increasing proliferation, and improving survival after 80% resection. Loss of EGFR expression is rate limiting for liver regeneration in obesity. Therapies directed at increasing EGFR in steatosis might promote liver regeneration and survival following hepatic resection or transplantation.

KEYWORDS:

epidermal growth factor receptor; gene transfer; hepatectomy; microarray; proliferation; steatosis

PMID:
28655714
PMCID:
PMC5668597
DOI:
10.1152/ajpendo.00032.2017
[Indexed for MEDLINE]
Free PMC Article

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