Biol. Pharm. Bull., 28(7),1192-1196, July 2005

Regular Articles

A New Retinoid-Like Compound That Activates Peroxisome Proliferator-Activated Receptors and Lowers Blood Glucose in Diabetic Mice

Tuo DENG,^a,b Song SHAN,^b Zhi-Bin LI,^b Zhong-Wen WU,^b Chen-Zhong LIAO,^b Ben KO,^cXian-Ping LU,^b Jing CHENG,^a,b and Zhi-Qiang NING^*,b

^a Department of Biological Science and Biotechnology, Tsinghua University; Beijing: ^b Chipscreen Biosciences Ltd., Research Institute of Tsinghua University; Shenzhen: and ^c Institute of Molecular Biology, University of Hong Kong; Hongkong, China. * To whom correspondence should be addressed. e-mail: zqning@chipscreen.com

Retinoid X receptor (RXR) forms heterodimers with peroxisome proliferator-activated receptors (PPARs, with subtypes of α, δ and γ), 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 PPARγ 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.

Key words synthetic compound; peroxisome proliferator-activated receptor; retinoid X receptor; type 2 diabetes