Erschienen:
[Erscheinungsort nicht ermittelbar]: Inst för laboratoriemedicin / Dept of Laboratory Medicine, 2013
Sprache:
Englisch
Identifikator:
Entstehung:
Hochschulschrift:
Dissertation, Inst för laboratoriemedicin / Dept of Laboratory Medicine, 2013
Anmerkungen:
Beschreibung:
Cholesterol carries multiple biological functions in the body, and imbalanced cholesterol metabolism lead s to atherosclerosis and cardiovascular diseases. The present thesis aims to extend the knowled ge of cholesterol metabolic regulation mediated by nuclear receptor LXRs and bile acids, two major players in the homeostasis of body cholesterol. In the first paper, we aim to unders tand how liver X receptor (LXR) regulates cholesterol metabolism in the intestine, in particular to compare the effects of the two isoforms, LXR α and LXR β on dietary cholestero l absorption and serum lipoprotein profiles. We find th at selective activation of LXR β enhances dietary cholesterol absorption in mice, whic h is accompanied by increased apoB lipoprotein cholesterol in the circulation. We also find that LXR α and LXR β compensate for each other in the trans criptional regulation of intestinal Abcg5, Abca1 and Npc1l1. Furthermore, the he patic enzymes Cyp7a1 and Cyp8b1 are differently modulated upon systemic LXR isoform activation. Given the contribution of the hydrophobic bile acid profile in the intestine, these changes together with the net differences in biliary cholesterol output may partially explain the isoform mediated changes in cholest erol absorption. Our findings reinforce the non-redundant function of LXR α and LXR β , and suggest that selective activation of LXR β as anti-atherogenic therapy may lead to undesired metabolic adverse effects. Bile acid synthesis represents the cr ucial elimination pathway for excess cholesterol. The negative feedback regul ation by end-product hydrophobic bile acids has been well established, involvin g the activation of nuclear receptor FXR, and a subsequent upregulatio n of SHP and Fgf15 for the suppression of bile acid synthesis in mice (Fgf19 as human counterp art). However, the role of hydrophilic bile acids in such context has largely b een ignored. By using a cholic acid (CA) deficient mouse model and different bile acid-modulating regimes, we define MCAs as FXR antagonistic bile acids, which counteract the FXR activation by hydrophobic bile acids. By modulating the enterohepatic circulation of bile acids, the positive feedback mechanism regulates bile acid homeostasis without employing the hormonal effect of Fgf15, although such an effect is likely to exist. This finding is of fundamental importance for the understating of bile acid metabolism in both humans and mice, as the Fgf15/19 negativ e feedback mechanism is believed to operate in both species. Paper III explores the therapeutic potential of CA depletion on systemic cholesterol overloading by using second generation antisense oligonucleotides (ASOs). Several ASOs targeting Cyp8b1, the enzyme responsible for CA production, have been used in the study. In mice, we observe a si gnificant reduction of the CA fraction in the biliary bile acid prof ile under ASO treatment. This reduction is accompanied by resistance to liver cholesterol accumula tion and an athero-protective lipoprotein profile upon cholesterol overloading. The da ta suggest the feasibility of using second generation ASOs as therapeutic targ et for cholesterol homeostasis, although a careful systematic study is needed to address the clinical aspect in human subjects.