Growth hormone and PPARa in the regulation of lipoprotein metabolism

Sammanfattning: In humans, apolipoprotein B (apoB)-100 is produced in the liver and apoB-48 is formed in the intestine. In the rat, however, the two forms of apoB are produced in the liver, leading to the formation of VLDL consisting of either apoB-48 or apoB-100. The mRNA for apoB-48 is produced by insertion of a stop codon in the mRNA for apoB-100, an enzyme-dependent event called apoB mRNA editing. From previous results, it is clear that growth hormone (GH) treatment in vivo stimulates the VLDL secretion in both rats and humans. However, during GH treatment, the liver is exposed to increased levels of insulin and fatty acids, which have been shown to increase VLDL secretion. Using primary rat hepatic cell cultures, GH incubation increased the apoB mRNA editing and triglyceride synthesis and decreased the apoB-100 secretion. Moreover, GH increased the secretion of apoB-48-VLDL and combined incubation with oleic acid had an additive effect. The importance of increased insulin secretion for the effect of GH in vivo was investigated in hypophysectomised (Hx) rats. Increased insulin levels did not mediate the observed effects of GH on serum lipoprotein levels. However, GH treatment increased the hepatic triglyceride secretion rate, an effect that was blunted by insulin treatment. Both GH and insulin increased the expression of lipogenic enzymes in Hx rats, indicating that these effects of GH could be mediated via increased insulin secretion. GH was found to decrease the expression of peroxisome proliferator-activated receptor a (PPARa) both in hepatocyte cultures and in Hx rats. In spite of decreased PPARa levels, GH increased the expression of liver fatty acid binding protein. The importance of PPARa for VLDL production was investigated in PPARa null mice. PPARa-deficient hepatocytes had an increased capacity for apoB and VLDL secretion. Female, in contrast to male PPARa null mice had increased hepatic triglyceride secretion rate and serum apoB levels. Moreover, when fed a high-fat diet, male PPARa null mice displayed increased serum apoB and LDL cholesterol levels.In summary, GH was found to have direct effects on apoB and VLDL production and secretion and increased insulin levels could not explain most of the effects of GH in vivo. GH decreased PPARa expression both in vitro and in vivo. PPARa null mice have higher secretion and serum levels of apoB-containing lipoproteins.