Hormonal regulation of hepatic cholesterol and lipoprotein metabolism : effects of estrogen and growth hormone

Coronary heart disease is the result of the progression of atherosclerotic lesions, and represents the major cause of death in western countries. Age, male sex, plasma cholesterol, hypertension and smoking are major risk factors for atherosclerosis. Of these, an increased level of plasma cholesterol within low density lipoproteins is of particular importance. It is therefore important to understand how plasma cholesterol is regulated. This study aimed to increase our understanding of the role of growth hormone and estrogen, and their interplay, in the regulation of hepatic cholesterol and lipoprotein metabolism by studying the effects of these hormones both in vitro and in vivo. The following conclusions could be drawn. * GH specifically induces the low density lipoprotein receptor (LDLR) in vitro, both at the protein and the mRNA level. This induction is mediated by GH receptors, and is independent of insulin-like growth factor-I release. * Hypophysectomy reduces the activity of important structures regulating hepatic cholesterol metabolism (cholesterol 7[alpha]-hydroxylase, hydroxy-methylglutaryl-coenzyme A reductase, and LDLR), and also decreases the fecal excretion of bile acids. * GH stimulates the cholesterol 7[alpha]-hydroxylase activity and bile acid synthesis in rats, and is important to maintain a normal plasma lipoprotein pattern. * The age-dependent hyperlipidemic lipoprotein profile can be reversed by GH infusion * The effects of estrogen on lipid metabolism are biphasic in female rats. A reduction in plasma total, LDL and HDL cholesterol, together with an enhanced hepatic LDLR expression, occurs at supraphysiological doses. Estrogen at low doses stimulates cholesterol 7[alpha]-hydroxylase and hydroxy-methylglutaryl-coenzyme A reductase activities. * The stimulation of hepatic LDLR by high-dose estrogen involves estrogen receptors, since concomitant treatment with antiestrogens abolished the LDLR stimulation, both at the protein and at the mRNA level. * Continuous infusion, but not pulse injections, of GH increases the hepatic estrogen receptor expression in male rats. * The feminization of the plasma lipoprotein pattern by continuous GH infusion involves estrogen receptors since the treatment with antiestrogen completely blocked the effects of GH infusion on HDL. Our results indicate that, also under physiological conditions, growth hormone and estrogen are important factors in the regulation of hepatic cholesterol and lipoprotein metabolism in the rat