Bovine growth hormone-transgenic mice have major alterations in hepatic expression of metabolic genes.
Transgenic mice overexpressing growth hormone (GH) have been extensively used to study the chronic effects of elevated serum levels of GH. GH is known to have many acute effects in the liver, but little is known about the chronic effects of GH overexpression on hepatic gene expression. Therefore, we used DNA microarray to compare gene expression in livers from bovine GH (bGH)-transgenic mice and littermates. Hepatic expression of peroxisome proliferator-activated receptor-alpha (PPARalpha) and genes involved in fatty acid activation, peroxisomal and mitochondrial beta-oxidation, and production of ketone bodies was decreased. In line with this expression profile, bGH-transgenic mice had a reduced ability to form ketone bodies in both the fed and fasted states. Although the bGH mice were hyperinsulinemic, the expression of sterol regulatory element-binding protein (SREBP)-1 and most lipogenic enzymes regulated by SREBP-1 was reduced, indicating that these mice are different from other insulin-resistant models with respect to expression of SREBP-1 and its downstream genes. This study also provides several candidate genes for the well-known association between elevated GH levels and cardiovascular disease, e.g., decreased expression of scavenger receptor class B type I, hepatic lipase, and serum paraoxonase and increased expression of serum amyloid A-3 protein. We conclude that bGH-transgenic mice display marked changes in hepatic genes coding for metabolic enzymes and suggest that GH directly or indirectly regulates many of these hepatic genes via decreased expression of PPARalpha and SREBP-1.
Olsson
Bob
B
Department of Physiology, Göteborg University, SE-405 30 Goteborg, Sweden. bob.olsson@medic.gu.se
Bohlooly-Y
Mohammad
M
Brusehed
Ola
O
Isaksson
Olle G P
OG
Ahrén
Bo
B
Olofsson
Sven-Olof
SO
Oscarsson
Jan
J
Törnell
Jan
J
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D002417:Cattle; D004268:DNA-Binding Proteins / Q000235:genetics; D005227:Fatty Acids / Q000097:blood; D015971:Gene Expression Regulation, Enzymologic; D013006:Growth Hormone / Q000235:genetics*; D006946:Hyperinsulinism / Q000503:physiopathology; D007657:Ketone Bodies / Q000097:blood; D008099:Liver / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000235:genetics
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D007657:Ketone Bodies; D018160:Receptors, Cytoplasmic and Nuclear; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D013006:Growth Hormone