title: Bile acids enhance the activity of the insulin receptor and glycogen synthase in primary rodent hepatocytes.
abstract: Previously, we demonstrated that deoxycholic acid (DCA)-induced ERK1/2 and AKT signaling in primary hepatocytes is a protective response. In the present study, we examined the regulation of the phosphatidylinositol 3 (PI3) kinase/AKT/glycogen synthase (kinase) 3 (GSK3)/glycogen synthase (GS) pathway by bile acids. In primary hepatocytes, DCA activated ERBB1 (the epidermal growth factor receptor), ERBB2, and the insulin receptor, but not the insulin-like growth factor 1 (IGF-1) receptor. DCA-induced activation of the insulin receptor correlated with enhanced phosphorylation of insulin receptor substrate 1, effects that were both blocked by the insulin receptor inhibitor AG1024 and by expression of the dominant negative IGF-1 receptor (K1003R), which inhibited in trans. Expression of the dominant negative IGF-1 receptor (K1003R) also abolished DCA-induced AKT activation. Bile acid-induced activation of AKT and phosphorylation of GSK3 were blunted by the ERBB1 inhibitor AG1478 and abolished by AG1024. Bile acids caused activation of GS to a similar level induced by insulin (50 nM); both were blocked by inhibition of insulin receptor function and the PI3 kinase/AKT/GSK3 pathway. In conclusion, these findings suggest that bile acids and insulin may cooperate to regulate glucose storage in hepatocytes.
authors.affiliation: Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA 23298-0058, USA. pdent@hsc.vcu.edu
authors.forename: Song Iy
authors.initials: SI
authors.lastname: Han
authors.forename: Elaine
authors.initials: E
authors.lastname: Studer
authors.forename: Seema
authors.initials: S
authors.lastname: Gupta
authors.forename: Youwen
authors.initials: Y
authors.lastname: Fang
authors.forename: Liang
authors.initials: L
authors.lastname: Qiao
authors.forename: Weiqun
authors.initials: W
authors.lastname: Li
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Philip B
authors.initials: PB
authors.lastname: Hylemon
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D018773:Genes, erbB-1 / Q000502:physiology; D018734:Genes, erbB-2 / Q000502:physiology; D005822:Genetic Vectors; D005947:Glucose / Q000378:metabolism; D006006:Glycogen Synthase / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; D005947:Glucose; D006006:Glycogen Synthase; D038362:Glycogen Synthase Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; C494920:Akt1 protein, rat