Xiaoling Jin1, Teresa A Zimmers2, Yanlin Jiang2, Daniel P Milgrom2, Zongxiu Zhang1, Leonidas G Koniaris3. 1. Department of Surgery, Thomas Jefferson University School of Medicine, Philadelphia, PA, USA. 2. Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA. 3. Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: lkoniari@iu.edu.
Abstract
BACKGROUND: Patients with fatty liver have delayed regenerative responses, increased hepatocellular injury, and increased risk for perioperative mortality. Currently, no clinical therapy exists to prevent liver failure or improve regeneration in patients with fatty liver. Previously we demonstrated that obese mice have markedly reduced levels of epidermal growth factor receptor in liver. We sought to identify pharmacologic agents to increase epidermal growth factor receptor expression to improve hepatic regeneration in the setting of fatty liver resection. METHODS: Lean (20% calories from fat) and diet-induced obese mice (60% calories from fat) were subjected to 70% or 80% hepatectomy. RESULTS: Using the BaseSpace Correlation Engine of deposited gene arrays we identified agents that increased hepatic epidermal growth factor receptor. Meloxicam was identified as inducing epidermal growth factor receptor expression across species. Meloxicam improved hepatic steatosis in diet-induced obese mice both grossly and histologically. Immunohistochemistry and Western blot analysis demonstrated that meloxicam pretreatment of diet-induced obese mice dramatically increased epidermal growth factor receptor protein expression in hepatocytes. After 70% hepatectomy, meloxicam pretreatment ameliorated liver injury and significantly accelerated mitotic rates of hepatocytes in obese mice. Recovery of liver mass was accelerated in obese mice pretreated with meloxicam (by 26% at 24 hours and 38% at 48 hours, respectively). After 80% hepatectomy, survival was dramatically increased with meloxicam treatment. CONCLUSION: Low epidermal growth factor receptor expression is a common feature of fatty liver disease. Meloxicam restores epidermal growth factor receptor expression in steatotic hepatocytes. Meloxicam pretreatment may be applied to improve outcome after fatty liver resection or transplantation with steatotic graft.
BACKGROUND:Patients with fatty liver have delayed regenerative responses, increased hepatocellular injury, and increased risk for perioperative mortality. Currently, no clinical therapy exists to prevent liver failure or improve regeneration in patients with fatty liver. Previously we demonstrated that obesemice have markedly reduced levels of epidermal growth factor receptor in liver. We sought to identify pharmacologic agents to increase epidermal growth factor receptor expression to improve hepatic regeneration in the setting of fatty liver resection. METHODS: Lean (20% calories from fat) and diet-induced obesemice (60% calories from fat) were subjected to 70% or 80% hepatectomy. RESULTS: Using the BaseSpace Correlation Engine of deposited gene arrays we identified agents that increased hepatic epidermal growth factor receptor. Meloxicam was identified as inducing epidermal growth factor receptor expression across species. Meloxicam improved hepatic steatosis in diet-induced obesemice both grossly and histologically. Immunohistochemistry and Western blot analysis demonstrated that meloxicam pretreatment of diet-induced obesemice dramatically increased epidermal growth factor receptor protein expression in hepatocytes. After 70% hepatectomy, meloxicam pretreatment ameliorated liver injury and significantly accelerated mitotic rates of hepatocytes in obesemice. Recovery of liver mass was accelerated in obesemice pretreated with meloxicam (by 26% at 24 hours and 38% at 48 hours, respectively). After 80% hepatectomy, survival was dramatically increased with meloxicam treatment. CONCLUSION: Low epidermal growth factor receptor expression is a common feature of fatty liver disease. Meloxicam restores epidermal growth factor receptor expression in steatotic hepatocytes. Meloxicam pretreatment may be applied to improve outcome after fatty liver resection or transplantation with steatotic graft.
Authors: Weiwei Wei; Olaf Dirsch; Anna Lawson Mclean; Sara Zafarnia; Michael Schwier; Uta Dahmen Journal: Eur Surg Res Date: 2014-11-12 Impact factor: 1.745
Authors: Astrit R Hamza; Avdyl S Krasniqi; Pramod Kadaba Srinivasan; Mamdouh Afify; Christian Bleilevens; Uwe Klinge; René H Tolba Journal: World J Gastroenterol Date: 2014-10-28 Impact factor: 5.742
Authors: Xiaoling Jin; Teresa A Zimmers; Eduardo A Perez; Robert H Pierce; Zongxiu Zhang; Leonidas G Koniaris Journal: Hepatology Date: 2006-03 Impact factor: 17.425