Growth hormone and PPARalpha in the regulation of genes involved in hepatic lipid metabolism

Abstract: Growth hormone (GH) plays a key role in the regulation of lipid and lipoprotein metabolism. Its sexually dimorphic secretory pattern regulates many sex-differentiated functions in the liver, such as triglyceride synthesis and VLDL secretion. GH also increases insulin secretion, and the importance of increased insulin levels for the effects of GH in vivo was therefore investigated in hypophysectomised (Hx) rats. GH increased the hepatic triglyceride secretion rate and triglyceride content, as well as fatty acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD-1) and sterol regulatory element binding protein-1c (SREBP-1c) mRNA expression. Insulin suppressed the effect of GH on hepatic triglyceride secretion rate and content, but this was not through changed gene expression of lipogenic enzymes or microsomal triglyceride transfer protein (MTP), the rate-limiting protein in VLDL assembly. The regulation of lipogenic genes and MTP by the sex-differentiated GH secretory pattern was studied both in Hx rats administered GH in a mode that mimics either the female or male plasma pattern of GH, and in intact males feminised with respect to the plasma pattern of GH. SREBP-1c, FAS, glycerol-3-phosphate acyltransferase (GPAT) and MTP levels were higher in females compared to males and specifically upregulated by the female-like GH plasma pattern in Hx rats. The expression of SCD-1 mRNA was not sex-differentiated and increased by GH irrespective of administration mode. Only FAS and GPAT mRNA levels were increased in males with feminised GH plasma pattern, possibly due to decreased insulin sensitivity. Increased expression of FAS, GPAT and MTP could therefore help to explain the previously described stimulatory effects of female sex and GH secretory pattern on VLDL assembly and secretion. Hepatic MTP expression and activity were also increased by the peroxisome proliferator-activated receptor alpha (PPARalpha) agonist WY 14,643 (WY), both in vivo (mice and rats) and in vitro (primary mouse and rat hepatocyte cultures). The increase in MTP expression was paralleled by a change in apoB-100 secretion, which shows that the stimulatory effect of WY on apoB-100 secretion could be mediated by MTP.