A new retinoid-like compound that activates peroxisome proliferator-activated receptors and lowers blood glucose in diabetic mice.
Retinoid X receptor (RXR) forms heterodimers with peroxisome proliferator-activated receptors (PPARs, with subtypes of alpha, delta and gamma), and the heterodimers can be activated by either an RXR or a PPAR subtype-specific ligand. Based on the chemical structure of the RXR natural ligand, 9-cis-retinoic acid (9-cis-RA), we designed and synthesized a retinoid-like compound, CS018. In vitro characterizations by cell-based reporter gene assays indicated that CS018 activated RXR homodimers and the heterodimers of RXR with PPARs, but not with farnesoid X-activated receptor (FXR) and liver X-activated receptor (LXR). Furthermore, RT-PCR results showed that CS018 induced the expression of the PPARgamma target genes, CD36 and lipoprotein lipase (LPL). In vivo studies on the diabetic db/db mice demonstrated that CS018 dramatically lowered the animal blood glucose levels. CS018 thus may represent a new retinoid-like compound that activates RXR/PPARs and has potential therapeutic applications in type 2 diabetes and other metabolic diseases.
Deng
Tuo
T
Department of Biological Science and Biotechnology, Tsinghua University, Beijing, China.
Shan
Song
S
Li
Zhi-Bin
ZB
Wu
Zhong-Wen
ZW
Liao
Chen-Zhong
CZ
Ko
Ben
B
Lu
Xian-Ping
XP
Cheng
Jing
J
Ning
Zhi-Qiang
ZQ
D000475:Alkenes / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000032:analysis*; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000097:blood*; D019281:Dimerization; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology*; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D012176:Retinoids / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000475:Alkenes; D001786:Blood Glucose; D017931:DNA Primers; D009281:Naphthalenes; D047492:Peroxisome Proliferator-Activated Receptors; D012176:Retinoids; C504648:ethyl(E,E,E)-7-(2-n-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-3-yl)-6-fluorp-3-methylocta-2,4,6-trienoate