作者: Sopher, Bryce L ; Flores, April L ; Torres, Mark-Joseph Manalang ; Yeo, Gene W ; Akimov, Sergey S ; Magnuson, Gavin K ; Miranda, Helen C ; Liu, Patrick P ; Tsunemi, Taiji ; La Spada, Albert R ; Arbez, Nicolas ; Dickey, Audrey S ; Lomas, Nicole ; Gaasterland, Terry ; Arreola, Martin ; Masliah, Eliezer ; Pinkerton, Anthony B ; Lazarowski, Eduardo R ; Sampat, Kunal R ; Buttgereit, Anne ; Gilmore-Hall, Stephen K ; Ross, Christopher A ; Pineda, Victor V

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which encodes a polyglutamine tract in the HTT protein. We found that peroxisome proliferator-activated receptor delta (PPAR-δ) interacts with HTT and that mutant HTT represses PPAR-δ-mediated transactivation. Increased PPAR-δ transactivation ameliorated mitochondrial dysfunction and improved cell survival of neurons from mouse models of HD. Expression of dominant-negative PPAR-δ in the central nervous system of mice was sufficient to induce motor dysfunction, neurodegeneration, mitochondrial abnormalities and transcriptional alterations that recapitulated HD-like phenotypes. Expression of dominant-negative PPAR-δ specifically in the striatum of medium spiny neurons in mice yielded HD-like motor phenotypes, accompanied by striatal neuron loss. In mouse models of HD, pharmacologic activation of PPAR-δ using the agonist KD3010 improved motor function, reduced neurodegeneration and increased survival. PPAR-δ activation also reduced HTT-induced neurotoxicity in vitro and in medium spiny-like neurons generated from stem cells derived from individuals with HD, indicating that PPAR-δ activation may be beneficial in HD and related disorders.

2012-05-22·Proceedings of the National Academy of Sciences1区 · 综合性期刊

Protection from liver fibrosis by a peroxisome proliferator-activated receptor δ agonist

1区 · 综合性期刊

Article

作者: Taura, Kojiro ; Yu, Elizabeth ; Evans, Ronald M. ; Schnabl, Bernd ; Paik, Yong-Han ; Haimerl, Michael ; Downes, Michael ; Sirlin, Claude ; Iwaisako, Keiko ; Kodama, Yuzo ; Yu, Ruth T. ; Brenner, David A.

Peroxisome proliferator-activated receptor delta (PPARδ), a member of the nuclear receptor family, is emerging as a key metabolic regulator with pleiotropic actions on various tissues including fat, skeletal muscle, and liver. Here we show that the PPARδ agonist KD3010, but not the well-validated GW501516, dramatically ameliorates liver injury induced by carbon tetrachloride (CCl 4 ) injections. Deposition of extracellular matrix proteins was lower in the KD3010-treated group than in the vehicle- or GW501516-treated group. Interestingly, profibrogenic connective tissue growth factor was induced significantly by GW501516, but not by KD3010, following CCl 4 treatment. The hepatoprotective and antifibrotic effect of KD3010 was confirmed in a model of cholestasis-induced liver injury and fibrosis using bile duct ligation for 3 wk. Primary hepatocytes treated with KD3010 but not GW501516 were protected from starvation or CCl 4 -induced cell death, in part because of reduced reactive oxygen species production. In conclusion, our data demonstrate that an orally active PPARδ agonist has hepatoprotective and antifibrotic effects in animal models of liver fibrosis, suggesting a possible mechanistic and therapeutic approach in treating patients with chronic liver diseases.

100 项与 KD-3010 相关的药物交易

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