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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Pfeifer, T; Buchebner, M; Chandak, PG; Patankar, J; Kratzer, A; Obrowsky, S; Rechberger, GN; Kadam, RS; Kompella, UB; Kostner, GM; Kratky, D; Levak-Frank, S.
Synthetic LXR agonist suppresses endogenous cholesterol biosynthesis and efficiently lowers plasma cholesterol.
Curr Pharm Biotechnol. 2011; 12(2):285-292
Doi: 10.2174/138920111794295774
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- Führende Autor*innen der Med Uni Graz
- Levak Sanja
- Co-Autor*innen der Med Uni Graz
- Chandak Prakash Gopal Das
- Kostner Gerhard
- Kratky Dagmar
- Obrowsky Sascha
- Patankar Jay Vasant
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- Abstract:
- The liver X receptors (LXRs) are key regulators of genes involved in cholesterol homeostasis. Natural ligands and activators of LXRs are oxysterols. Numerous steroidal and non-steroidal synthetic LXR ligands are under development as potential drugs for individuals suffering from lipid disorders. N,N-dimethyl-3β-hydroxycholenamide (DMHCA) is a steroidal ligand of LXRs that exerts anti-atherogenic effects in apolipoprotein E-deficient mice without causing negative side effects such as liver steatosis or hypertriglyceridemia. In this report, we investigated the consequences of DMHCA treatment on cholesterol homeostasis in vivo and in vitro. Despite its hydrophobicity, DMHCA is readily absorbed by C57BL/6 mice and taken up by intestinal cells, the lung, heart and kidneys, but is undetectable in the brain. DMHCA significantly reduces cholesterol absorption and uptake in duodenum and jejunum of the small intestine and in turn leads to a reduction of plasma cholesterol by 24%. The most striking finding of this study is that DMHCA inhibited the enzyme 3β-hydroxysterol-Δ24-reductase resulting in an accumulation of desmosterol in the plasma and in feces. Thus, the reduction of plasma cholesterol was due to a block in the final step of cholesterol biosynthesis. Taken together, DMHCA is an interesting compound with properties distinct from other LXR ligands and might be used to study desmosterol-mediated effects in cells and tissues.
- Find related publications in this database (using NLM MeSH Indexing)
- Androstenes - pharmacokinetics
- Animals -
- Anticholesteremic Agents - pharmacokinetics
- Cell Survival - drug effects
- Cholesterol - biosynthesis
- Cholic Acids - pharmacokinetics
- Desmosterol - metabolism
- Enzyme Inhibitors - pharmacokinetics
- Fatty Liver - chemically induced
- Feces -
- Hep G2 Cells -
- Humans -
- Intestines - drug effects
- Lipid Metabolism - drug effects
- Lipogenesis - drug effects
- Male -
- Mice -
- Mice, Inbred C57BL -
- Nerve Tissue Proteins - antagonists & inhibitors
- Orphan Nuclear Receptors - agonists
- Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors
- Find related publications in this database (Keywords)
- Cholesterol absorption
- cholesterol biosynthesis
- desmosterol
- DHCR24
- DMHCA
- liver X receptor