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PPARγ is essential for protection against nonalcoholic steatohepatitis

Gene Therapy volume 17, pages 790–798 (2010)Cite this article

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Abstract

Peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor that regulates lipid metabolism and inflammatory responses. Certain PPARγ ligands improve nonalcoholic steatohepatitis (NASH). The role of PPARγ itself in NASH remains poorly understood. The functional consequences of PPARγ in the development of steatohepatitis through gene deficiency or gene overexpression of PPARγ delivered by adenovirus (Ad-PPARγ) were examined. Our results show that PPARγ-deficient (PPARγ+/−) mice fed the methionine- and choline-deficient (MCD) diet developed more severe steatohepatitis than wild-type mice, and were unaffected by PPARγ ligand rosiglitazone. Overexpression of PPARγ delivered by Ad-PPARγ attenuated steatohepatitis. This effect was associated with redistribution of fatty acid from liver to adipose tissue by enhancing expression of fatty acid uptake genes (fatty acid binding protein-4 (aP2), fatty acid translocase (CD36), lipoprotein lipase (LPL) and fatty acid transport protein-1 (FATP-1)) and lipogenic genes (sterol regulatory element binding protein isoform-1 (SREBP-1) and stearoyl-CoA desaturase isoform-1 (SCD-1)) in adipose tissue and to a lesser extent in liver. The anti-steatohepatitis action of PPARγ was also mediated via regulating adipokines through suppressing tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and inducing adiponectin. Moreover, PPARγ activation suppressed hepatic lipoperoxide and reduced hepatic pro-inflammatory cytokines (TNF-α and IL-6) production. In conclusion, PPARγ is an important endogenous regulator and potential therapeutic target for nutritional steatohepatitis.

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Abbreviations

ALT:

alanine aminotransferase

aP2:

fatty acid binding protein-4

FATP:

fatty acid transport protein

CD36:

fatty acid translocase

LPL:

lipoprotein lipase

MCD:

methionine and choline deficient

NASH:

nonalcoholic steatohepatitis

PPARγ:

peroxisome proliferator-activated receptor-γ

SCD-1:

stearoyl-CoA desaturase isoform-1

SREBP-1:

sterol regulatory element binding protein isoform-1

TG:

triglyceride

WAT:

white adipose tissue

TNF-α:

tumor necrosis factor-α

IL-6:

interleukin-6

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Acknowledgements

This project was funded by a Research Grants Council Competitive Earmarked Research Grants CUHK 478207 and CUHK478108.

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  1. Institute of Digestive Disease and Department of Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China

    C W Wu, E S H Chu, C N Y Lam, A S L Cheng, C W Lee, V W S Wong, J J Y Sung & J Yu

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  1. C W Wu
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Correspondence to J Yu.

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Wu, C., Chu, E., Lam, C. et al. PPARγ is essential for protection against nonalcoholic steatohepatitis. Gene Ther 17, 790–798 (2010). https://doi.org/10.1038/gt.2010.41

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