Meloxicam increases epidermal growth factor receptor expression improving survival after hepatic resection in diet-induced obese mice

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.