Growth hormone regulation of LFABP and PPARa. Genes involved in hepatic lipid metabolism

Abstract

Growth hormone (GH) is known to have several important effects in the control of metabolism. The aim of these studies was to investigate how GH regulates genes involved in fatty acid transport and metabolism in the liver and the interaction between GH and fatty acids in this regulation. Liver fatty acid binding protein (LFABP) is important for cellular fatty acid uptake and transport and peroxisome proliferator activated receptor (PPAR)a is a fatty acid activated nuclear receptor that regulates several genes in hepatic lipid metabolism, including LFABP. Hypophysectomized (Hx) rats and primary hepatocytes cultured in serum free medium were used to study the hormonal and dietary regulation of LFABP and PPARa. GH was shown to be an important regulator of cytosolic LFABP levels and LFABP mRNA in the liver. The effect of GH on LFABP mRNA levels in vivo was reproduced in vitro and found to be dependent on increased transcription of the gene and the presence of insulin. Fatty acids and GH had additive effects on LFABP mRNA levels in vitro and on cytosolic LFABP levels in vivo. Hepatic PPARa mRNA levels increased by hypophysectomy and GH decreased PPARa mRNA in both Hx rats and cultured hepatocytes, indicating that the effect of GH on LFABP is not mediated via changed expression of PPARa. Male rats had higher levels of PPARa mRNA than female rats. The results of hypophysectomy and gonadectomy of both sexes indicated that pituitary dependent hormones have a more marked inhibitory effect on PPARa mRNA expression in female rats than in male rats. The sex difference in GH secretion could not explain the sex differences in either PPARa or LFABP gene expression. C/EBPa is a potential transcription factor for several GH regulated genes in the liver. C/EBPa mRNA and protein increased after GH treatment of cultured rat hepatocytes and this increase was accompanied by increased DNA binding of C/EBPa, indicating that increased C/EBPa may mediate the effects of GH on e.g. LFABP gene expression. In summary, GH and fatty acids interact in the regulation of hepatic genes involved in fatty acid transport and metabolism.