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. DESIGN: 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.

Nyckelord

Animals

Body Weight/drug effects

Cytochrome P-450 Enzyme System/genetics

Diacylglycerol O-Acyltransferase/genetics

Fatty Acids/metabolism

Female

Gene Expression/*drug effects

Growth Hormone/*pharmacology

Insulin-Like Growth Factor I/metabolism

Lipid Metabolism/*drug effects/genetics

Lipids/blood

Lipoproteins

VLDL/*metabolism

Liver/drug effects/*metabolism

Male

Mice

Mice

Mutant Strains

Oxidation-Reduction

PPAR alpha/genetics/*physiology

PPAR gamma/genetics

RNA

Messenger/analysis/metabolism

Sex Factors

Triglycerides/analysis/metabolism

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)