title: The dysfunction of hepatic transcriptional factors in mice with Huntington's Disease.
abstract: Huntington's Disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The resultant mutant Htt protein (mHtt) forms aggregates in the brain and several peripheral tissues (e.g., the liver), and causes devastating widespread pathology. Since aggregates of mHtt have been found in the liver, defects in liver function might contribute to peripheral abnormalities in HD mice. We previously reported that two crucial transcription factors PPARγ (peroxisome proliferator-activated receptor-γ) and C/EBPα (CCAAT/enhancer-binding protein α) are potential therapeutic targets of HD. We herein demonstrate that the transcript level of PPARγ was markedly downregulated in the livers of a transgenic mouse model of HD (R6/2). Treatment of R6/2 mice with an agonist of PPARγ (thiazolidinedione, TZD) normalized the reduced PPARγ transcript. By reducing Htt aggregates and thereby ameliorating the recruitment of PPARγ into Htt aggregates, TZD treatment also elevated the availability of the PPARγ level and subsequently normalized the expression of its downstream genes [including PGC-1α (PPAR coactivator-1α) and several mitochondrial genes] and C/EBPα in the liver. The aforementioned protective effects appeared to be exerted by a direct activation of the PPARγ agonist (rosiglitazone) because rosiglitazone reduced mHtt aggregates and rescued energy deficiency in a hepatoma cell line (HepG2). These findings show that the impairment of PPARγ contributes to the liver dysfunction observed in HD. Treatment with PPARγ agents (TZD and rosiglitazone) enhanced the function of PPARγ, and might lead to therapeutic benefits.
authors.affiliation: Graduate Institute of Biotechnology, Chinese Culture University, Taipei 111, Taiwan. cmcphd@gmail.com
authors.forename: Ming-Chang
authors.initials: MC
authors.lastname: Chiang
authors.forename: Yijuang
authors.initials: Y
authors.lastname: Chern
authors.forename: Chiun-Gung
authors.initials: CG
authors.lastname: Juo
mesh_terms: D000818:Animals; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D045162:Thiazolidinediones / Q000627:therapeutic use*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D045162:Thiazolidinediones; D015534:Trans-Activators; D014157:Transcription Factors; C089946:2,4-thiazolidinedione