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The dysfunction of hepatic transcriptional factors in mice with Huntington's Disease.

Authors: Chiang, MC  Chern, Y  Juo, CG 
Citation: Chiang MC, etal., Biochim Biophys Acta. 2011 Sep;1812(9):1111-20. Epub 2011 May 30.
Pubmed: (View Article at PubMed) PMID:21651979
DOI: Full-text: DOI:10.1016/j.bbadis.2011.05.006

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 PPARgamma (peroxisome proliferator-activated receptor-gamma) and C/EBPalpha (CCAAT/enhancer-binding protein alpha) are potential therapeutic targets of HD. We herein demonstrate that the transcript level of PPARgamma was markedly downregulated in the livers of a transgenic mouse model of HD (R6/2). Treatment of R6/2 mice with an agonist of PPARgamma (thiazolidinedione, TZD) normalized the reduced PPARgamma transcript. By reducing Htt aggregates and thereby ameliorating the recruitment of PPARgamma into Htt aggregates, TZD treatment also elevated the availability of the PPARgamma level and subsequently normalized the expression of its downstream genes [including PGC-1alpha (PPAR coactivator-1alpha) and several mitochondrial genes] and C/EBPalpha in the liver. The aforementioned protective effects appeared to be exerted by a direct activation of the PPARgamma agonist (rosiglitazone) because rosiglitazone reduced mHtt aggregates and rescued energy deficiency in a hepatoma cell line (HepG2). These findings show that the impairment of PPARgamma contributes to the liver dysfunction observed in HD. Treatment with PPARgamma agents (TZD and rosiglitazone) enhanced the function of PPARgamma, and might lead to therapeutic benefits.


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RGD Object Information
RGD ID: 6484269
Created: 2012-06-19
Species: All species
Last Modified: 2012-06-19
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.