Pretreatment with FK506 up-regulates insulin receptors in regenerating rat liver.
This report examines the effect of FK506 pretreatment on liver insulin receptor expression in partially (70%) hepatectomized rats. FK506 pretreatment led to an increased insulin receptor number 24 hours after hepatectomy, detected by means of insulin binding and cross-linking procedures. This increase was related to enhanced insulin receptor expression determined by in vitro mRNA translation and Western blot techniques. We also tested the functionality of the expressed insulin receptors by [(3)H] thymidine incorporation into DNA in insulin-stimulated hepatocytes. The results show that FK506 pretreatment elicits an increase in the amount of insulin receptor alpha-subunits as measured by Western blot. Maximum alpha-subunit expression recorded 24 hours after surgery was preceded by increased insulin receptor mRNA levels, which were detected 6 hours after hepatectomy. Moreover, in FK506-pretreated rat hepatocytes, obtained from remnant livers 24 hours after partial hepatectomy (PH), the increase in insulin receptor number was associated with improved sensitivity to the hormone. However, in both experimental groups (FK506-pretreated and nonpretreated rats), the sensitivity of hepatocytes toward epidermal growth factor (EGF) showed no significant change, which suggests a specific effect of FK506 on insulin receptor expression. In conclusion, our findings suggest that FK506 pretreatment induces insulin receptor expression in regenerating rat liver and promotes liver regeneration in hepatectomized rats.
Unidad de Toxicología Molecular Hepática, Departamento de Bioquímica y Biología Molecular, Universidad de Alcalá, E-28871, Alcalá de Henares, Spain.
Oscar
O
Escribano
María Dolores
MD
Fernández-Moreno
María Jesús
MJ
Piña
Jesús
J
Fueyo
César
C
Menor
Irene Dolores
ID
Román
Luis G
LG
Guijarro
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001786:Blood Glucose; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000166:cytology; D008115:Liver Regeneration / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D012709:Serum Albumin; D016559:Tacrolimus / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007166:Immunosuppressive Agents; D007328:Insulin; D012333:RNA, Messenger; D012709:Serum Albumin; D004815:Epidermal Growth Factor; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D011972:Receptor, Insulin; D016559:Tacrolimus