Effects of glucose metabolism on the regulation of genes of fatty acid synthesis and triglyceride secretion in the liver.
Glucose disposal induces a signal that modulates the transcriptional regulation of genes involved in the glycolysis and lipogenesis pathways. To investigate the role of glucose metabolism on hepatic gene expression independently from insulin action, we overexpressed glucokinase, the limiting enzyme in the glycolysis pathway, in the liver of streptozotocin-induced type 1 diabetic rats. By microarray analysis, we observed that critical genes such as liver-type pyruvate kinase, malic enzyme, fatty acid synthase, and stearoyl-CoA desaturase 1 were enhanced multiple-fold, whereas genes involved in mitochondrial fatty acid oxidation and the Krebs cycle were downregulated. Despite the increase in expression of fatty acid synthesis genes and the presence of steatosis, no major alterations to the levels of genes involved in VLDL assembly and secretion, such as diacylglycerol acyltransferases 1 and 2 and microsomal triglyceride transfer protein, were observed. Overall, our data suggest that the gene expression pattern induced by glucose metabolism favors fatty acid storage in the liver rather than secretion into the circulation.
Morral
Núria
N
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. nmorralc@iupui.edu
Edenberg
Howard J
HJ
Witting
Scott R
SR
Altomonte
Jennifer
J
Chu
Tearina
T
Brown
Matthew
M
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology; D005227:Fatty Acids / Q000096:biosynthesis*; D051858:Forkhead Transcription Factors / Q000235:genetics; D020869:Gene Expression Profiling; D005941:Glucokinase / Q000096:biosynthesis / Q000235:genetics*; D005947:Glucose / Q000378:metabolism*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins; D047495:PPAR gamma / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000235:genetics; D051381:Rats; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism*; D000071161:Forkhead Box Protein O1
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005227:Fatty Acids; D051858:Forkhead Transcription Factors; D005941:Glucokinase; D005947:Glucose; D051542:Hepatocyte Nuclear Factor 3-beta; D009419:Nerve Tissue Proteins; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D051779:Sterol Regulatory Element Binding Proteins; D014157:Transcription Factors; D014280:Triglycerides; C496504:Foxa2 protein, rat; C442825:Mlxipl protein, rat; C501429:Ppargc1a protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1