Importance of PPAR alpha for the effects of growth hormone on hepatic lipid and lipoprotein metabolism.
OBJECTIVE
Growth hormone (GH) enhances lipolysis in adipose tissue, thereby increasing the flux of fatty acids to other tissues. Moreover, GH increases hepatic triglyceride synthesis and secretion in rats and decreases the action of peroxisome proliferator-activated receptor (PPAR)alpha. PPARalpha is activated by fatty acids and regulates hepatic lipid metabolism in rodents. The aim of this study was to investigate the importance of PPARalpha for the effects of GH on hepatic gene expression and lipoprotein metabolism.


METHODS
Bovine GH was given as a continuous infusion (5mg/kg/day) for 7 days to PPARalpha-null and wild-type (wt) mice. Plasma and liver lipids and hepatic gene expression were measured. In separate experiments, hepatic triglyceride secretion was measured.


RESULTS
GH treatment decreased hepatic triglyceride content and increased hepatic triglyceride secretion rate and serum cholesterol levels. Furthermore, GH increased hepatic acylCoA:diacylglycerol acyltransferase (DGAT)2 mRNA levels, but decreased the hepatic mRNA expression of acyl-CoA oxidase, medium-chain acyl-CoA dehydrogenase and PPARgamma1. All these GH effects were independent of PPARalpha. However, the effect of GH on Cyp4a10, PPARgamma2, and DGAT1 was different between the genotypes. GH treatment decreased Cyp4a10 mRNA expression in wt mice, but increased the expression in PPARalpha-null mice. In contrast, GH decreased the expression of DGAT1 and PPARgamma2 in PPARalpha-null mice, but not in wt mice.


CONCLUSIONS
Most of the effects of GH on lipid and lipoprotein metabolism were independent of PPARalpha. However, GH had unique effects on Cyp4a10, DGAT1, and PPARgamma2 gene expression in PPARalpha-null mice showing cross-talk between GH and PPARalpha signalling in vivo.
Ljungberg
Anna
A
Wallenberg Laboratory for Cardiovascular Research, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
Lindén
Daniel
D
Améen
Caroline
C
Bergström
Göran
G
Oscarsson
Jan
J
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D013006:Growth Hormone / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008055:Lipids / Q000097:blood; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000235:genetics / Q000502:physiology*; D047495:PPAR gamma / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012737:Sex Factors; D014280:Triglycerides / Q000032:analysis / Q000378:metabolism
C512110:Cyp4a10 protein, mouse; D005227:Fatty Acids; D008055:Lipids; D008079:Lipoproteins, VLDL; D047493:PPAR alpha; D047495:PPAR gamma; D012333:RNA, Messenger; D014280:Triglycerides; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase