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Elevated levels of plasma cholesterol, mainly in low density lipoproteins (LDL), are a major risk factor for coronary heart disease. The level of plasma LDL cholesterol (LDL-C) is largely dependent on the number of hepatic LDL receptors (LDLRs). Increased numbers of LDLRs lead to higher uptake of LDL particles and lower concentration of plasma LDL-C. Proprotein convertase subtilisin Kexin Type 9 (PCSK9) is a novel key regulator in cholesterol metabolism. PCSK9 reduces the number of available hepatic LDLRs leading to increased plasma levels of LDL-C. Inhibition of PCSK9 has a great potential as a cholesterol-lowering agent. However, the physiological role of PCSK9 is largely unknown. In this study we investigated the regulation of PCSK9 in rats and humans, by hormones and diets and during the diurnal phases. We can show that: I) Reduced bile acid synthesis, but not changes in PCSK9, likely contributes to the age-dependent hypercholesterolemia in rats. Treatment with growth hormone (GH) restores bile acid synthesis to juvenile levels and upregulate