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      GH administration rescues fatty liver regeneration impairment by restoring GH/EGFR pathway deficiency.

      Endocrinology
      Animals, Blotting, Western, Cell Proliferation, drug effects, Choline, metabolism, Diet, Down-Regulation, Fatty Liver, physiopathology, prevention & control, Hepatectomy, methods, Hepatocytes, pathology, Human Growth Hormone, administration & dosage, blood, deficiency, Humans, Liver, surgery, Male, Methionine, Mice, Mice, Inbred C57BL, Mice, Obese, Non-alcoholic Fatty Liver Disease, Obesity, Receptor, Epidermal Growth Factor, genetics, Reverse Transcriptase Polymerase Chain Reaction, STAT3 Transcription Factor, Signal Transduction, physiology, Triglycerides

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          Abstract

          GH pathway has been shown to play a major role in liver regeneration through the control of epidermal growth factor receptor (EGFR) activation. This pathway is down-regulated in nonalcoholic fatty liver disease. Because regeneration is known to be impaired in fatty livers, we wondered whether a deregulation of the GH/EGFR pathway could explain this deficiency. Hepatic EGFR expression and triglyceride levels were quantified in liver biopsies of 32 obese patients with different degrees of steatosis. We showed a significant inverse correlation between liver EGFR expression and the level of hepatic steatosis. GH/EGFR down-regulation was also demonstrated in 2 steatosis mouse models, a genetic (ob/ob) and a methionine and choline-deficient diet mouse model, in correlation with liver regeneration defect. ob/ob mice exhibited a more severe liver regeneration defect after partial hepatectomy (PH) than methionine and choline-deficient diet-fed mice, a difference that could be explained by a decrease in signal transducer and activator of transcription 3 phosphorylation 32 hours after PH. Having checked that GH deficiency accounted for the GH signaling pathway down-regulation in the liver of ob/ob mice, we showed that GH administration in these mice led to a partial rescue in hepatocyte proliferation after PH associated with a concomitant restoration of liver EGFR expression and signal transducer and activator of trnascription 3 activation. In conclusion, we propose that the GH/EGFR pathway down-regulation is a general mechanism responsible for liver regeneration deficiency associated with steatosis, which could be partially rescued by GH administration.

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