title: HDL is redundant for adrenal steroidogenesis in LDLR knockout mice with a human-like lipoprotein profile.
abstract: The contribution of HDL to adrenal steroidogenesis appears to be different between mice and humans. In the current study, we tested the hypothesis that a difference in lipoprotein profile may be the underlying cause. Hereto, we determined the impact of HDL deficiency on the adrenal glucocorticoid output in genetically modified mice with a human-like lipoprotein profile. Genetic deletion of APOA1 in LDL receptor (LDLR) knockout mice was associated with HDL deficiency and a parallel increase in the level of cholesterol associated with nonHDL fractions. Despite a compensatory increase in the adrenal relative mRNA expression levels of the cholesterol synthesis gene, HMG-CoA reductase, adrenals from APOA1/LDLR double knockout mice were severely depleted of neutral lipids, as compared with those of control LDLR knockout mice. However, basal corticosterone levels and the adrenal glucocorticoid response to stress were not different between the two types of mice. In conclusion, we have shown that HDL is not critical for proper adrenal glucocorticoid function when mice are provided with a human-like lipoprotein profile. Our findings provide the first experimental evidence that APOB-containing lipoproteins may facilitate adrenal steroidogenesis, in an LDLR-independent manner, in vivo in mice.
authors.affiliation: Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, 2333CC Leiden, The Netherlands Hoekstra@lacdr.leidenuniv.nl.
authors.forename: Menno
authors.initials: M
authors.lastname: Hoekstra
authors.affiliation: Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, 2333CC Leiden, The Netherlands.
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
mesh_terms: D000818:Animals; D008076:Cholesterol, HDL / Q000097:blood*; D003345:Corticosterone / Q000097:blood; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics*
chemical_list: D008076:Cholesterol, HDL; D011973:Receptors, LDL; D003345:Corticosterone
keywords: cholesterol; corticosterone; gene expression; high density lipoprotein; low density lipoprotein; low density lipoprotein receptor; steroid hormones