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

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Title:	The dysfunction of hepatic transcriptional factors in mice with Huntington's Disease
Authors:	Chiang, Ming-Chang Chern, Yijuang Juo, Chiun-Gung
Contributors:	生物科技研究所
Keywords:	NEURODEGENERATIVE DISEASES ACTIVATED-RECEPTOR-GAMMA UREA CYCLE DEFICIENCY PEROXISOME-PROLIFERATOR PPAR-GAMMA MUTANT HUNTINGTIN MOUSE MODEL C/EBP-ALPHA MITOCHONDRIAL DYSFUNCTION GENE-EXPRESSION
Date:	2011-09
Issue Date:	2012-09-07 14:49:40 (UTC+8)
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 PPAR gamma (peroxisome proliferator-activated receptor-gamma) and C/EBP alpha (CCAAT/enhancer-binding protein alpha) are potential therapeutic targets of HD. We herein demonstrate that the transcript level of PPAR gamma was markedly downregulated in the livers of a transgenic mouse model of HD (R6/2). Treatment of R6/2 mice with an agonist of PPAR gamma (thiazolidinedione, TZD) normalized the reduced PPAR gamma transcript. By reducing Htt aggregates and thereby ameliorating the recruitment of PPAR gamma into Htt aggregates, TZD treatment also elevated the availability of the PPAR gamma level and subsequently normalized the expression of its downstream genes [including PGC-1 alpha (PPAR coactivator-1 alpha) and several mitochondrial genes] and C/EBP alpha in the liver. The aforementioned protective effects appeared to be exerted by a direct activation of the PPAR gamma agonist (rosiglitazone) because rosiglitazone reduced mHtt aggregates and rescued energy deficiency in a hepatoma cell line (HepG2). These findings show that the impairment of PPAR gamma contributes to the liver dysfunction observed in HD. Treatment with PPAR gamma agents (TZD and rosiglitazone) enhanced the function of PPAR gamma, and might lead to therapeutic benefits. (C) 2011 Elsevier B.V. All rights reserved.
Relation:	Source: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE Volume: 1812 Issue: 9 Pages: 1111-1120
Appears in Collections:	[Graduate Institute of Biotechnology ] journal articles

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