GH administration rescues fatty liver regeneration impairment by restoring GH/EGFR pathway deficiency.
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.
Inserm (A.C.H., A.Z.-S., C.P.-B., V.F., N.H., C.V., K.B., V.B., H.G., J.-E.G.), U1016, Institut Cochin, 75014, Paris, France; CNRS (A.C.H., A.Z.-S., C.P.-B., V.F., N.H., C.V., K.B., V.B., H.G., J.-E.G.), UMR8104, 75014, Paris, France; Université Paris Descartes (A.C.H., A.Z.-S., C.P.-B., V.F., N.H., C.V., K.B., V.B., H.G., J.-E.G.), Sorbonne Paris Cité, Faculté de Médecine 75006, Paris, France; and Service de Chirurgie Digestive et Métabolique (N.H., M.Z., C.V.), Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Seine-St-Denis, Hôpital Jean Verdier, 93140, Bondy, France.
A
A
Collin de l'Hortet
A
A
Zerrad-Saadi
C
C
Prip-Buus
V
V
Fauveau
N
N
Helmy
M
M
Ziol
C
C
Vons
K
K
Billot
V
V
Baud
Hélène
H
Gilgenkrantz
Jacques-Emmanuel
JE
Guidotti
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002794:Choline / Q000378:metabolism; D004032:Diet; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D006498:Hepatectomy / Q000379:methods; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019382:Human Growth Hormone / Q000008:administration & dosage* / Q000097:blood / Q000172:deficiency; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000601:surgery; D008297:Male; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism
D050796:STAT3 Transcription Factor; D014280:Triglycerides; D019382:Human Growth Hormone; D008715:Methionine; D066246:ErbB Receptors; D002794:Choline