title: Synthetic LXR agonist suppresses endogenous cholesterol biosynthesis and efficiently lowers plasma cholesterol.
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.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/3, Graz, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pfeifer
authors.forename: Marlene
authors.initials: M
authors.lastname: Buchebner
authors.forename: Prakash G
authors.initials: PG
authors.lastname: Chandak
authors.forename: Jay
authors.initials: J
authors.lastname: Patankar
authors.forename: Adelheid
authors.initials: A
authors.lastname: Kratzer
authors.forename: Sascha
authors.initials: S
authors.lastname: Obrowsky
authors.forename: Gerald N
authors.initials: GN
authors.lastname: Rechberger
authors.forename: Rajendra S
authors.initials: RS
authors.lastname: Kadam
authors.forename: Uday B
authors.initials: UB
authors.lastname: Kompella
authors.forename: Gerhard M
authors.initials: GM
authors.lastname: Kostner
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
authors.forename: Sanja
authors.initials: S
authors.lastname: Levak-Frank
mesh_terms: D000736:Androstenes / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D002793:Cholic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D003897:Desmosterol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D005234:Fatty Liver / Q000139:chemically induced; D005243:Feces; D056945:Hep G2 Cells; D006801:Humans; D007422:Intestines / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects*; D050155:Lipogenesis / Q000187:drug effects*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors
chemical_list: D000736:Androstenes; D000924:Anticholesteremic Agents; D002793:Cholic Acids; D004791:Enzyme Inhibitors; D000071518:Liver X Receptors; C413890:N,N-dimethyl-3-hydroxy-5-cholenamide; D009419:Nerve Tissue Proteins; D057093:Orphan Nuclear Receptors; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D003897:Desmosterol; D002784:Cholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C437069:3beta-hydroxysterol delta24-reductase