Surgical liver resection can cure patients with a variety of primary and metastatic hepatic tumors. Surgery on fatty liver is associated with delayed hepatocyte proliferation and increased hepatocyte necroapoptosis, leading to a markedly increased rate of liver failure, morbidity and mortality. To date the molecular mechanisms responsible for defective recovery from liver surgery in the setting of fatty liver remain poorly understood. No therapies exist to prevent liver failure or improve recovery after fatty liver surgery. Our long-term goals are to improve survival after fatty liver surgery, to provde greater rates of curative fatty liver resections, and to expand the donor pool for living-donor livr transplantation. The objectives of this specific application are to investigate two new potential therapeutic target for fatty liver recovery after resection and to extend those findings into a pre clinical large animal model. Our studies show that fatty liver expresses reduced levels of EGFR, a critical mediator of hepatocyte proliferation and recovery of liver mass and function after injur. Acute resveratrol restores EGFR expression. Both genetic restoration of EGFR and resveratrol restores survival after fatty liver resection. Based on these data, our hypothesis is that reduced hepatocyte EGFR signaling leads directly to reduced survival and impaired recovery after hepatectomy. Rescue of survival after fatty liver surgery by resveratrol is mediated at least partly by EGFR up-regulation, but also likely through other pathways. To test this hypothesis, we will: 1) investigate the role of EGFR and define its key downstream signaling pathways in the hepatocyte response to fatty liver resection;2) investigate the EGFR-dependent and independent mechanisms by which resveratrol rescues recovery from fatty liver surgery;and 3) establish the efficacy, tolerability and toxicity of resveratrol in an obese mini-pig model of fatt liver surgery. Once these studies are complete we will have defined the extent to which EGFR and downstream pathways can restore normal liver regeneration in fatty liver and completed preclinical studies to introduce resveratrol as a potential therapy.

Public Health Relevance

Patients with fatty liver have much higher rates of illness and death after liver surgery. Using mouse and pig models, this pre-clinical study will examine two new potential therapies, EGFR and resveratrol, to improve outcomes after fatty liver surgery!

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK096167-02
Application #
8535753
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Doo, Edward
Project Start
2012-09-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$325,326
Indirect Cost
$115,438
Name
Thomas Jefferson University
Department
Surgery
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Pons, Marianne; Koniaris, Leonidas G; Moe, Sharon M et al. (2018) GDF11 induces kidney fibrosis, renal cell epithelial-to-mesenchymal transition, and kidney dysfunction and failure. Surgery 164:262-273
Milgrom, Daniel P; Koniaris, Leonidas G; Valsangkar, Nakul P et al. (2018) An Assessment of the Academic Impact of Shock Society Members. Shock 49:508-513
Kays, Joshua K; Shahda, Safi; Stanley, Melissa et al. (2018) Three cachexia phenotypes and the impact of fat-only loss on survival in FOLFIRINOX therapy for pancreatic cancer. J Cachexia Sarcopenia Muscle 9:673-684
Jin, Xiaoling; Zimmers, Teresa A; Jiang, Yanlin et al. (2018) Meloxicam increases epidermal growth factor receptor expression improving survival after hepatic resection in diet-induced obese mice. Surgery 163:1264-1271
Zimmers, Teresa A; Jin, Xiaoling; Zhang, Zongxiu et al. (2017) Epidermal growth factor receptor restoration rescues the fatty liver regeneration in mice. Am J Physiol Endocrinol Metab 313:E440-E449