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Molecular mechanisms underlying the effect of pioglitazone therapy in Non-Alcoholic Steatohepatitis (NASH)

Background and Aim: A recent randomised double-blind placebocontrolled trial (RCT) demonstrated that Pioglitazone therapy was effective in reducing hepatocellular injury and fibrosis in subjects with NASH. We aimed to investigate the molecular mechanisms underlying the effects of Pioglitazone in...

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Main Authors: Abdul Rahim, Roslina, Aithal, Guruprasad Padur, Macdonald, Ian A., Bennett, Andrew J.
Format: Article
Language:English
Published: Elsevier, Inc. 2009
Subjects:
R Medicine (General)
RA Public aspects of medicine
RB Pathology
RC Internal medicine
RT Nursing
Online Access:http://irep.iium.edu.my/52366/1/EASL%202009.pdf
http://irep.iium.edu.my/52366/
http://www.journal-of-hepatology.eu/article/S0168-8278(09)60694-2/abstract
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spelling my.iium.irep.523662016-10-20T03:46:50Z http://irep.iium.edu.my/52366/ Molecular mechanisms underlying the effect of pioglitazone therapy in Non-Alcoholic Steatohepatitis (NASH) Abdul Rahim, Roslina Aithal, Guruprasad Padur Macdonald, Ian A. Bennett, Andrew J. R Medicine (General) RA Public aspects of medicine RB Pathology RC Internal medicine RT Nursing Background and Aim: A recent randomised double-blind placebocontrolled trial (RCT) demonstrated that Pioglitazone therapy was effective in reducing hepatocellular injury and fibrosis in subjects with NASH. We aimed to investigate the molecular mechanisms underlying the effects of Pioglitazone in NASH. Methods: Liver biopsy samples collected from 46 non-diabetic subjects before and after 1-year treatment with 30 mg/day of Pioglitazone or placebo were used for RNA and protein extraction. 200 ng of total RNA was used to synthesise cDNA for gene expression using Taqman RealTime Polymerase Chain Reaction (RT-PCR). Results: See Table 1. Table 1: Effects of 12 months of Pioglitazone treatment on gene expression. Target gene Pre-trial (n = 22) Pioglitazone (n = 12) Placebo (n = 12) P Value ChREBP 2.156 ±0.435b 3.971 ±1.049b 2.117 ±0.520 0.049b SREBP-1C 1.478 ±0.258a 2.150 ±0.610c 0.310 ±0.062a,c 0.022a, 0.002c CPT-1 0.492 ±0.156 0.793 ±0.275 0.476 ±0.136 NS PDK4 1.679 ±0.369 2.137 ±0.481 0.842 ±0.295 NS PK2 1.549 ±0.363 1.317 ±0.377 1.227 ±0.337 NS GCK 0.658 ±0.284 0.794 ±0.374 1.401 ±0.725 NS Gene expression values are normalised using the geometric mean of the reference genes (beta actin and hydroxymethylbilane synthase). Data are presented as mean ± SEM. Carbohydrate regulatory element binding protein (ChREBP), Sterol regulatory element binding protein-1C (SREBP-1C), Carnitine palmitoyl transferase-1 (CPT-1), Pyruvate dehydrogenase kinase 4 (PDK4), Pyruvate kinase 2 (PK2) and Glucokinase (GCK). aPre-trial vs Placebo; bPre-trial vs Pioglitazone; cPioglitazone vs placebo) Conclusions: Pioglitazone therapy caused a significant upregulation of both ChREBP and SREBP-1C gene which are both involved in the transcriptional regulation of lipogenesis. Conversely, patients given placebo showed marked reduction in the SREBP-1C by the end of the trial period. It is unclear at present as to the mechanism by which Pioglitazone therapy increases lipogenic transcription factor levels. These findings may reflect the improved whole body insulin sensitivity observed in the Pioglitazone treated group. Alternatively the increase in ChREBP and SREBP-1C may be caused by direct effects of Pioglitazone activation of PPAR- g (Peroxisome proliferator-activated receptor- g) in the liver. Elsevier, Inc. 2009-04 Article REM application/pdf en http://irep.iium.edu.my/52366/1/EASL%202009.pdf Abdul Rahim, Roslina and Aithal, Guruprasad Padur and Macdonald, Ian A. and Bennett, Andrew J. (2009) Molecular mechanisms underlying the effect of pioglitazone therapy in Non-Alcoholic Steatohepatitis (NASH). Journal of Hepatology, 50 (supp. 1). S254. ISSN 0168-8278 http://www.journal-of-hepatology.eu/article/S0168-8278(09)60694-2/abstract
institution Universiti Islam Antarabangsa Malaysia
building IIUM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider International Islamic University Malaysia
content_source IIUM Repository (IREP)
url_provider http://irep.iium.edu.my/
language English
topic R Medicine (General)
RA Public aspects of medicine
RB Pathology
RC Internal medicine
RT Nursing
spellingShingle R Medicine (General)
RA Public aspects of medicine
RB Pathology
RC Internal medicine
RT Nursing
Abdul Rahim, Roslina
Aithal, Guruprasad Padur
Macdonald, Ian A.
Bennett, Andrew J.
Molecular mechanisms underlying the effect of pioglitazone therapy in Non-Alcoholic Steatohepatitis (NASH)
description Background and Aim: A recent randomised double-blind placebocontrolled trial (RCT) demonstrated that Pioglitazone therapy was effective in reducing hepatocellular injury and fibrosis in subjects with NASH. We aimed to investigate the molecular mechanisms underlying the effects of Pioglitazone in NASH. Methods: Liver biopsy samples collected from 46 non-diabetic subjects before and after 1-year treatment with 30 mg/day of Pioglitazone or placebo were used for RNA and protein extraction. 200 ng of total RNA was used to synthesise cDNA for gene expression using Taqman RealTime Polymerase Chain Reaction (RT-PCR). Results: See Table 1. Table 1: Effects of 12 months of Pioglitazone treatment on gene expression. Target gene Pre-trial (n = 22) Pioglitazone (n = 12) Placebo (n = 12) P Value ChREBP 2.156 ±0.435b 3.971 ±1.049b 2.117 ±0.520 0.049b SREBP-1C 1.478 ±0.258a 2.150 ±0.610c 0.310 ±0.062a,c 0.022a, 0.002c CPT-1 0.492 ±0.156 0.793 ±0.275 0.476 ±0.136 NS PDK4 1.679 ±0.369 2.137 ±0.481 0.842 ±0.295 NS PK2 1.549 ±0.363 1.317 ±0.377 1.227 ±0.337 NS GCK 0.658 ±0.284 0.794 ±0.374 1.401 ±0.725 NS Gene expression values are normalised using the geometric mean of the reference genes (beta actin and hydroxymethylbilane synthase). Data are presented as mean ± SEM. Carbohydrate regulatory element binding protein (ChREBP), Sterol regulatory element binding protein-1C (SREBP-1C), Carnitine palmitoyl transferase-1 (CPT-1), Pyruvate dehydrogenase kinase 4 (PDK4), Pyruvate kinase 2 (PK2) and Glucokinase (GCK). aPre-trial vs Placebo; bPre-trial vs Pioglitazone; cPioglitazone vs placebo) Conclusions: Pioglitazone therapy caused a significant upregulation of both ChREBP and SREBP-1C gene which are both involved in the transcriptional regulation of lipogenesis. Conversely, patients given placebo showed marked reduction in the SREBP-1C by the end of the trial period. It is unclear at present as to the mechanism by which Pioglitazone therapy increases lipogenic transcription factor levels. These findings may reflect the improved whole body insulin sensitivity observed in the Pioglitazone treated group. Alternatively the increase in ChREBP and SREBP-1C may be caused by direct effects of Pioglitazone activation of PPAR- g (Peroxisome proliferator-activated receptor- g) in the liver.
format Article
author Abdul Rahim, Roslina
Aithal, Guruprasad Padur
Macdonald, Ian A.
Bennett, Andrew J.
author_facet Abdul Rahim, Roslina
Aithal, Guruprasad Padur
Macdonald, Ian A.
Bennett, Andrew J.
author_sort Abdul Rahim, Roslina
title Molecular mechanisms underlying the effect of pioglitazone therapy in Non-Alcoholic Steatohepatitis (NASH)
title_short Molecular mechanisms underlying the effect of pioglitazone therapy in Non-Alcoholic Steatohepatitis (NASH)
title_full Molecular mechanisms underlying the effect of pioglitazone therapy in Non-Alcoholic Steatohepatitis (NASH)
title_fullStr Molecular mechanisms underlying the effect of pioglitazone therapy in Non-Alcoholic Steatohepatitis (NASH)
title_full_unstemmed Molecular mechanisms underlying the effect of pioglitazone therapy in Non-Alcoholic Steatohepatitis (NASH)
title_sort molecular mechanisms underlying the effect of pioglitazone therapy in non-alcoholic steatohepatitis (nash)
publisher Elsevier, Inc.
publishDate 2009
url http://irep.iium.edu.my/52366/1/EASL%202009.pdf
http://irep.iium.edu.my/52366/
http://www.journal-of-hepatology.eu/article/S0168-8278(09)60694-2/abstract
_version_ 1643614150139576320
score 13.211869

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