A novel liver X receptor agonist establishes species differences in the regulation of cholesterol 7alpha-hydroxylase (CYP7a)
| Autor: | Samuel D. Wright, David E. Moller, Gaochao Zhou, Karen L. MacNaul, Patrick Xin, Carl P. Sparrow, Yu-Sheng Chao, My-Hanh Lam, Soumya P. Sahoo, Azriel Schmidt, Alex Elbrecht, Nancy S. Hayes, Linda J. Kelly, John G. Menke, Jianhua Wang, Joanne Baffic |
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| Rok vydání: | 2002 |
| Předmět: |
Transcriptional Activation
medicine.medical_specialty Receptors Retinoic Acid Receptors Cytoplasmic and Nuclear Cholesterol 7 alpha-hydroxylase Gene Expression Regulation Enzymologic Monocytes Rats Sprague-Dawley Endocrinology Species Specificity Internal medicine polycyclic compounds medicine Animals Humans Liver X receptor Receptor Cholesterol 7-alpha-Hydroxylase Triglycerides Liver X Receptors Phenylacetates Receptors Thyroid Hormone biology Apolipoprotein A-I Reverse Transcriptase Polymerase Chain Reaction Isoxazoles Blotting Northern Orphan Nuclear Receptors Molecular biology Recombinant Proteins Sterol regulatory element-binding protein Rats DNA-Binding Proteins Cholesterol Nuclear receptor ABCG1 ABCA1 Enzyme Induction Knockout mouse biology.protein Hepatocytes lipids (amino acids peptides and proteins) |
| Zdroj: | Endocrinology. 143(7) |
| ISSN: | 0013-7227 |
| Popis: | The liver X receptors, LXRalpha and LXRbeta, are members of the nuclear receptor superfamily. Originally identified as orphans, both receptor subtypes have since been shown to be activated by naturally occurring oxysterols. LXRalpha knockout mice fail to regulate cyp7a mRNA levels upon cholesterol feeding, implicating the role of this receptor in cholesterol homeostasis. LXR activation also induces the expression of the lipid pump involved in cholesterol efflux, the gene encoding ATP binding cassette protein A1 (ABCA1). Therefore, LXR is believed to be a sensor of cholesterol levels and a potential therapeutic target for atherosclerosis. Here we describe a synthetic molecule named F(3)MethylAA [3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-(4,5)-isoxazolyl)propylthio)-phenyl acetic acid] that is more potent than 22(R)-hydroxycholesterol in LXR in vitro assays. F(3)MethylAA is capable not only of inducing ABCA1 mRNA levels, but also increasing cholesterol efflux from THP-1 macrophages. In rat hepatocytes, F(3)MethylAA induced cyp7a mRNA, confirming conclusions from the knockout mouse studies. Furthermore, in rat in vivo studies, F(3)MethylAA induced liver cyp7a mRNA and enzyme activity. A critical species difference is also reported in that neither F(3)MethylAA nor 22(R)-hydroxycholesterol induced cyp7a in human primary hepatocytes. However, other LXR target genes, ABCA1, ABCG1, and SREBP1, were regulated. |
| Databáze: | OpenAIRE |
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