A novel liver X receptor agonist establishes species differences in the regulation of cholesterol 7alpha-hydroxylase (CYP7a).
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.
Menke
John G
JG
Molecular Endocrinology at Merck & Co., Rahway, New Jersey 07065, USA. John_Menke@merck.com
Macnaul
Karen L
KL
Hayes
Nancy S
NS
Baffic
Joanne
J
Chao
Yu-Sheng
YS
Elbrecht
Alex
A
Kelly
Linda J
LJ
Lam
My-Hanh
MH
Schmidt
Azriel
A
Sahoo
Soumya
S
Wang
Jianhua
J
Wright
Samuel D
SD
Xin
Patrick
P
Zhou
Gaochao
G
Moller
David E
DE
Sparrow
Carl P
CP
D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D015152:Blotting, Northern; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis* / Q000235:genetics*; D004268:DNA-Binding Proteins; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D000071518:Liver X Receptors; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D010648:Phenylacetates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D011988:Receptors, Thyroid Hormone / Q000819:agonists*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D015533:Transcriptional Activation / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism
C460362:3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-benzisoxazolyl)propylthio)phenylacetic acid; D016632:Apolipoprotein A-I; D004268:DNA-Binding Proteins; D007555:Isoxazoles; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D010648:Phenylacetates; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D011994:Recombinant Proteins; D014280:Triglycerides; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase