Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Pfeifer, T.
The impact of DMHCA, an oxysterol derived LXR ligand on cholesterol metabolism in mice
[ Dissertation ] Medical University of Graz; 2010. pp. 96
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- Autor*innen der Med Uni Graz:
- Pfeifer Thomas
- Betreuer*innen:
- Frank Sasa
- Levak Sanja
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- Abstract:
- Liver X receptor (LXR) agonists have the potential to treat atherosclerosis based on their ability to induce reverse cholesterol transport and decrease cholesterol absorption in the small intestine. However, the side effects like hepatic liver steatosis or apoptosis in pancreatic beta cells limit their pharmaceutical development. N,N-dimethyl-3ß-hydroxycholenamide (DMHCA) is a steroidal LXR ligand which was previously shown to bind LXR alpha and LXR beta without inducing SREBP1c in vitro. We confirmed this result in vivo after a short term DMHCA treatment (4 days) of C57Bl/6J mice and long term treatment (11weeks) with DMHCA in ApoE(-/-) mice reduced atherosclerosis plaque lesion. Furthermore, the effects of DMHCA on the reverse cholesterol transport, cholesterol absorption in the small intestine and lipogenesis in the liver and pancreatic beta cells has been investigated in comparison to an established LXR ligand T0901317. Within this PhD thesis I demonstrated that a 4-day treatment with DMHCA decreased fractional cholesterol absorption and increased fecal and billiary sterol loss due to upregulation of ABCG5/G8, Cyp7a1 and reduction of NPC1L1 in the small intestine. In contrast to other LXR agonists, DMHCA lowered plasma cholesterol levels. Therefore, the cholesterol biosynthesis in HepG2 cells has been measured and revealed that DMHCA indeed decreased endogenous cholesterol biosynthesis indicating its dual effects on the cholesterol metabolism. Moreover, a 4-day treatment with DMHCA led to the accumulation of desmosterol in the small intestine, liver, plasma and feces, suggesting that DMHCA might interact with DHCR24 on protein level. This finding was confirmed by in vitro DHCR24 activity assay and radioactive cholesterol biosynthesis experiments. In summary, these findings indicate that DMHCA has dual effects on cholesterol homeostasis that result in decreased plasma cholesterol concentration. DMHCA acts at least in part as an inhibitor of DHCR24, which leads to a reduction but not loss of cholesterol. No morphologic effects however, were observed in the DMHCA-treated mice. Thereby, it induces an increase in desmosterol concentration. The properties of DMHCA, which differ from those of other synthetic LXR agonists, make DMHCA an interesting substance to study desmosterol-mediated effects in cells. Its inability to induce lipogenic genes in contrast to non-steroidal agonists, as well as its suppressive effects on endogenous cholesterol biosynthesis project steroidal agonists as a better strategy for anti-atherosclerotic drugs.