Browsing by Author "Zhang, Zongxiu"

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    Epidermal growth factor receptor restoration rescues the fatty liver regeneration in mice
    (American Physiological Society, 2017-10-01) Zimmers, Teresa A.; Jin, Xiaoling; Zhang, Zongxiu; Jiang, Yanlin; Koniaris, Leonidas G.; Surgery, School of Medicine
    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.
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    Meloxicam increases epidermal growth factor receptor expression improving survival after hepatic resection in diet-induced obese mice
    (Elsevier, 2018-06) Jin, Xiaoling; Zimmers, Teresa A.; Jiang, Yanlin; Milgrom, Daniel P.; Zhang, Zongxiu; Koniaris, Leonidas G.; Surgery, School of Medicine
    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.