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Departments of 1Physiology and 2Medical Biochemistry, Göteborg University, SE-405 30 Goteborg; 3Research Center for Endocrinology and Metabolism, Department of Internal Medicine and 4Wallenberg Laboratory for Cardiovascular Disease, Sahlgrenska University Hospital, SE-413 45 Goteborg; 5AstraZeneca Transgenics and Comparative Genomics Center, AstraZeneca Research and Development, SE-431 83 Molndal; and 6Department 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
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