Bovine growth hormone-transgenic mice have major alterations in hepatic expression of metabolic genes

• Published in: American journal of physiology: endocrinology and metabolism 2003-09, Vol.285 (3), p.E504-E511
• Main Authors: Olsson, Bob, Bohlooly-Y, Mohammad, Brusehed, Ola, Isaksson, Olle G. P, Ahren, Bo, Olofsson, Sven-Olof, Oscarsson, Jan, Tornell, Jan
• Format: Article
• Language: English
• Subjects: Animals; Basic Medicine; Cattle; CCAAT-Enhancer-Binding Proteins - genetics; DNA microarray; DNA-Binding Proteins - genetics; element-binding protein; fatty acids; Fatty Acids - blood; Fysiologi; Gene Expression Regulation, Enzymologic; Growth Hormone - genetics; Hyperinsulinism - physiopathology; Ketone Bodies - blood; Liver - physiology; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; Mice, Transgenic; Oligonucleotide Array Sequence Analysis; peroxisome; Physiology; proliferator-activated receptor-alpha; Receptors, Cytoplasmic and Nuclear - genetics; Reverse Transcriptase Polymerase Chain Reaction; sterol regulatory; Sterol Regulatory Element Binding Protein 1; Transcription Factors - genetics; transgenic mice
• ISSN: 0193-1849; 1522-1555; 1522-1555
• DOI: 10.1152/ajpendo.00444.2002

Departments of 1 Physiology and 2 Medical Biochemistry, Göteborg University, SE-405 30 Goteborg; 3 Research Center for Endocrinology and Metabolism, Department of Internal Medicine and 4 Wallenberg Laboratory for Cardiovascular Disease, Sahlgrenska University Hospital, SE-413 45 Goteborg; 5 AstraZeneca Transgenics and Comparative Genomics Center, AstraZeneca Research and Development, SE-431 83 Molndal; and 6 Department of Medicine, Lund University, SE-221 84 Lund, Sweden Submitted 16 November 2002 ; accepted in final form 26 April 2003 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- (PPAR ) and genes involved in fatty acid activation, peroxisomal and mitochondrial -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 PPAR and SREBP-1. fatty acids; transgenic mice; DNA microarray; peroxisome proliferator-activated receptor- ; sterol regulatory element-binding protein Address for reprint requests and other correspondence: B. Olsson, Research Center, Endocrinology and Metabolism, Dept. of Internal Medicine, Göteborg Univ., Vita Straket 12, SE-405 30 Goteborg, Sweden (E-mail: bob.olsson{at}