Mechanisms behind the lipid-lowering effects of ACTH - Studies in different experimental models

Abstract Adrenocorticotrophic hormone (ACTH) has strong and direct lipid-lowering effects in man. All apoB-containing lipoproteins, i.e. VLDL, LDL, Lp(a), are reduced by 25-30%. In contrast, levels of HDL increase about 10%. In hepatic cell cultures, ACTH inhibits expression and secretion of apoB. In this thesis we corroborate that the reduced apoB synthesis, seen in hepatic cell systems, is also operative in vivo in man, using intestinal lipoprotein production after fat intake as a model system. We also observed that the inhibition of lipoprotein particle synthesis induced by ACTH did not result in impaired lipid processing and transport. We hypothesise that ACTH treatment leads to the production of fewer but larger lipoproteins, which is an attractive concept since recent data indicate that the adverse effects of hyperlipidemia is related to the number of atherogenic particles rather than to molar concentrations of plasma lipids, or lipoprotein lipid levels. In agreement with the findings in vivo, ACTH did not affect lipid synthesis or secretion from hepatic cell cultures. Taken together, these data strongly indicate that the effects of ACTH on lipoprotein metabolism are primarily a consequence of decreased production of apoB, and consequently on lipoprotein production and secretion. Since most hypolipidemic drugs act by facilitating the removal of lipoproteins and/or decrease lipid synthesis, ACTH or ACTH analogues may provide an attractive alternative or complement to currently available medications. When exploring possible animal models for more detailed mechanistic studies, we found that species differences in lipid transport made the rat an unsuitable model for further investigations. The effects of ACTH on diet-induced hyperlipidemia in the rabbit, however, were similar to those in man, providing an experimental tool for further studies of ACTH in vivo