title: A modest glucokinase overexpression in the liver promotes fed expression levels of glycolytic and lipogenic enzyme genes in the fasted state without altering SREBP-1c expression.
abstract: Hepatic genes crucial for carbohydrate and lipid homeostasis are regulated by insulin and glucose metabolism. However, the relative contributions of insulin and glucose to the regulation of metabolic gene expression are poorly defined in vivo. To address this issue, adenovirus-mediated hepatic overexpression of glucokinase was used to determine the effects of increased hepatic glucose metabolism on gene expression in fasted or ad libitum fed rats. In the fasted state, a 3 fold glucokinase overexpression was sufficient to mimic feeding-induced increases in pyruvate kinase and acetyl CoA carboxylase mRNA levels, demonstrating a primary role for glucose metabolism in the regulation of these genes in vivo. Conversely, glucokinase overexpression was unable to mimic feeding-induced alterations of fatty acid synthase, glucose-6-phosphate dehydrogenase, carnitine palmitoyl transferase I or PEPCK mRNAs, indicating insulin as the primary regulator of these genes. Interestingly, glucose-6-phosphatase mRNA was increased by glucokinase overexpression in both the fasted and fed states, providing evidence, under these conditions, for the dominance of glucose over insulin signaling for this gene in vivo. Importantly, glucokinase overexpression did not alter sterol regulatory element binding protein 1-c mRNA levels in vivo and glucose signaling did not alter the expression of this gene in primary hepatocytes. We conclude that a modest hepatic overexpression of glucokinase is sufficient to alter expression of metabolic genes without changing the expression of SREBP-1c.
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. dscott3@lsuhsc.edu
authors.forename: D K
authors.initials: DK
authors.lastname: Scott
authors.forename: J J
authors.initials: JJ
authors.lastname: Collier
authors.forename: T T T
authors.initials: TT
authors.lastname: Doan
authors.forename: A S
authors.initials: AS
authors.lastname: Bunnell
authors.forename: M C
authors.initials: MC
authors.lastname: Daniels
authors.forename: D T
authors.initials: DT
authors.lastname: Eckert
authors.forename: R M
authors.initials: RM
authors.lastname: O'Doherty
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis*; D002334:Carnitine O-Palmitoyltransferase / Q000096:biosynthesis; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D064429:Fatty Acid Synthases / Q000378:metabolism; D005786:Gene Expression Regulation; D005941:Glucokinase / Q000096:biosynthesis* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000096:biosynthesis; D008099:Liver / Q000201:enzymology*; D008954:Models, Biological; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000096:biosynthesis; D011770:Pyruvate Kinase / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1; D013997:Time Factors; D014157:Transcription Factors
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D012313:RNA; D005954:Glucosephosphate Dehydrogenase; D002334:Carnitine O-Palmitoyltransferase; D064429:Fatty Acid Synthases; D005941:Glucokinase; D011770:Pyruvate Kinase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose