GH Administration Rescues Fatty Liver Regeneration Impairment by Restoring GH/EGFR Pathway Deficiency

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.

Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration

“…Our observations demonstrated that the biological activities present in FGF15/19 can be harnessed in a new molecule termed Fibapo with improved kinetic and pharmacological properties. As recently proposed for growth hormone,53 the perioperative administration of FA, alone or in combination with other strategies such as weight loss, could improve the outcome of patients with steatotic organs that need resection.…”

Not So Giants: Mice Lacking Both Somatostatin and Cortistatin Have High GH Levels but Show No Changes in Growth Rate or IGF-1 Levels

“…Further support to the idea that the liver of our double-KO mice model had partial resistance to GH actions was obtained by measuring hepatic egf-r expression, a molecular marker reported to be highly sensitive to GH levels and to the pattern of GH delivery, and to be associated to liver resistance. In fact, Diaz et al (23) recently reported that continuous GH delivery in male mice suppresses egf-r, which was associated with a loss of hepatic GH responsiveness as observed in models with low GH levels [ie, ob/ob (24)]. Accordingly, double-SST/ CORT-KO mice with elevated GH levels in a feminized pattern displayed a markedly reduced hepatic egf-r expression, which would likely be accompanied by reduced hepatic GH responsiveness/partial GH resistance that may explain the lack of an IGF-1 rise in a model with high GH levels.…”

The biological activity of high-density lipoprotein fractions and their role in the development of cardiovascular diseases

“…В соответствии с этими данными маленькие плот-ные ЛПВП3 более устойчивы к окислительным модификациям по сравнению с крупными легкими ЛПВП2 [39,40]. ЛПВП за-щищают ЛПНП от окислительного повреждения одноэлектрон-ными окислителями через двухступенчатый механизм, включаю-щий передачу фосфолипидных гидроперекисей от ЛПНП к ЛПВП, которая регулируется жесткостью поверхностного моно-слоя ЛПВП, а также последующим восстановлением фосфоли-пидной гидроперекиси путем окисления метиониновых остатков апоА1 с образованием неактивных фосфолипидных гидроксидов [41,42].…”

“…Во-первых, восста-новление гидроперекисей липидов в гидроокиси более эффектив-но в ЛПВП3 по сравнению с ЛПВП2 [28], что объясняется повы-шенным содержанием апоА1 в маленьких плотных ЛПВП [42]. Более того, специфическая конформация апоА1 в ЛПВП3 может способствовать проведению окислительно-восстановительных реакций между метиониновыми остатками апоА1 и гидропереки-сью липидов.…”

“…Более того, специфическая конформация апоА1 в ЛПВП3 может способствовать проведению окислительно-восстановительных реакций между метиониновыми остатками апоА1 и гидропереки-сью липидов. Во-вторых, гидролиз короткоцепочечных окислен-ных фосфолипидов в ЛПВП под действием гидролитических фер-ментов также усиливается в маленьких плотных ЛПВП3 [42,43]. Этот эффект мог бы объяснятся активной ферментативной дея-тельностью PON1, ЛХАТ и ФАТ-ацетилгидролазы в ЛПВП3.…”