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PPARα agonist and metformin co-treatment ameliorates NASH in mice induced by a choline-deficient, amino acid-defined diet with 45% fat
We explored the beneficial effects of GW7647, a peroxisome proliferator activated receptor α (PPARα) agonist, and metformin, an anti-diabetic drug on an advanced nonalcoholic steatohepatitis (NASH) model in rodents and investigated the possible mechanisms involved. Mice were fed control chow or a ch...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658250/ https://www.ncbi.nlm.nih.gov/pubmed/33177546 http://dx.doi.org/10.1038/s41598-020-75805-z |
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author | Okishio, Shinya Yamaguchi, Kanji Ishiba, Hiroshi Tochiki, Nozomi Yano, Kota Takahashi, Aya Kataoka, Seita Okuda, Keiichiroh Seko, Yuya Liu, Yu Fujii, Hideki Takahashi, Daiki Ito, Yusuke Kamon, Junji Umemura, Atsushi Moriguchi, Michihisa Yasui, Kohichiroh Okanoue, Takeshi Itoh, Yoshito |
author_facet | Okishio, Shinya Yamaguchi, Kanji Ishiba, Hiroshi Tochiki, Nozomi Yano, Kota Takahashi, Aya Kataoka, Seita Okuda, Keiichiroh Seko, Yuya Liu, Yu Fujii, Hideki Takahashi, Daiki Ito, Yusuke Kamon, Junji Umemura, Atsushi Moriguchi, Michihisa Yasui, Kohichiroh Okanoue, Takeshi Itoh, Yoshito |
author_sort | Okishio, Shinya |
collection | PubMed |
description | We explored the beneficial effects of GW7647, a peroxisome proliferator activated receptor α (PPARα) agonist, and metformin, an anti-diabetic drug on an advanced nonalcoholic steatohepatitis (NASH) model in rodents and investigated the possible mechanisms involved. Mice were fed control chow or a choline-deficient l-amino acid-defined diet containing 45% fat (HF-CDAA). The mice fed HF-CDAA diets for 16 weeks were divided into four groups: the no treatment (HF-CDAA), HF-CDAA containing 1000 mg/kg metformin, HF-CDAA containing 10 mg/kg GW7647, and HF-CDAA with both metformin and GW7647 groups. Metformin alone slightly deteriorated the aspartate and alanine aminotransferase (AST/ALT) values, whereas co-treatment with GW7647 and metformin greatly suppressed liver injury and fibrosis via activation of the AMP-activated protein kinase (AMPK) pathway. Further study revealed that co-treatment decreased the expression of inflammatory-, fibrogenesis-, and endoplasmic reticulum (ER) stress-related genes and increased the oxidized nicotinamide adenine dinucleotide (NAD)/reduced nicotinamide adenine dinucleotide (NADH) ratio, suggesting the superiority of co-treatment due to restoration of mitochondrial function. The additive benefits of a PPARα agonist and metformin in a HF-CDAA diet-induced advanced NASH model was firstly demonstrated, possibly through restoration of mitochondrial function and AMPK activation, which finally resulted in suppression of hepatic inflammation, ER stress, then, fibrosis. |
format | Online Article Text |
id | pubmed-7658250 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-76582502020-11-12 PPARα agonist and metformin co-treatment ameliorates NASH in mice induced by a choline-deficient, amino acid-defined diet with 45% fat Okishio, Shinya Yamaguchi, Kanji Ishiba, Hiroshi Tochiki, Nozomi Yano, Kota Takahashi, Aya Kataoka, Seita Okuda, Keiichiroh Seko, Yuya Liu, Yu Fujii, Hideki Takahashi, Daiki Ito, Yusuke Kamon, Junji Umemura, Atsushi Moriguchi, Michihisa Yasui, Kohichiroh Okanoue, Takeshi Itoh, Yoshito Sci Rep Article We explored the beneficial effects of GW7647, a peroxisome proliferator activated receptor α (PPARα) agonist, and metformin, an anti-diabetic drug on an advanced nonalcoholic steatohepatitis (NASH) model in rodents and investigated the possible mechanisms involved. Mice were fed control chow or a choline-deficient l-amino acid-defined diet containing 45% fat (HF-CDAA). The mice fed HF-CDAA diets for 16 weeks were divided into four groups: the no treatment (HF-CDAA), HF-CDAA containing 1000 mg/kg metformin, HF-CDAA containing 10 mg/kg GW7647, and HF-CDAA with both metformin and GW7647 groups. Metformin alone slightly deteriorated the aspartate and alanine aminotransferase (AST/ALT) values, whereas co-treatment with GW7647 and metformin greatly suppressed liver injury and fibrosis via activation of the AMP-activated protein kinase (AMPK) pathway. Further study revealed that co-treatment decreased the expression of inflammatory-, fibrogenesis-, and endoplasmic reticulum (ER) stress-related genes and increased the oxidized nicotinamide adenine dinucleotide (NAD)/reduced nicotinamide adenine dinucleotide (NADH) ratio, suggesting the superiority of co-treatment due to restoration of mitochondrial function. The additive benefits of a PPARα agonist and metformin in a HF-CDAA diet-induced advanced NASH model was firstly demonstrated, possibly through restoration of mitochondrial function and AMPK activation, which finally resulted in suppression of hepatic inflammation, ER stress, then, fibrosis. Nature Publishing Group UK 2020-11-11 /pmc/articles/PMC7658250/ /pubmed/33177546 http://dx.doi.org/10.1038/s41598-020-75805-z Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Okishio, Shinya Yamaguchi, Kanji Ishiba, Hiroshi Tochiki, Nozomi Yano, Kota Takahashi, Aya Kataoka, Seita Okuda, Keiichiroh Seko, Yuya Liu, Yu Fujii, Hideki Takahashi, Daiki Ito, Yusuke Kamon, Junji Umemura, Atsushi Moriguchi, Michihisa Yasui, Kohichiroh Okanoue, Takeshi Itoh, Yoshito PPARα agonist and metformin co-treatment ameliorates NASH in mice induced by a choline-deficient, amino acid-defined diet with 45% fat |
title | PPARα agonist and metformin co-treatment ameliorates NASH in mice induced by a choline-deficient, amino acid-defined diet with 45% fat |
title_full | PPARα agonist and metformin co-treatment ameliorates NASH in mice induced by a choline-deficient, amino acid-defined diet with 45% fat |
title_fullStr | PPARα agonist and metformin co-treatment ameliorates NASH in mice induced by a choline-deficient, amino acid-defined diet with 45% fat |
title_full_unstemmed | PPARα agonist and metformin co-treatment ameliorates NASH in mice induced by a choline-deficient, amino acid-defined diet with 45% fat |
title_short | PPARα agonist and metformin co-treatment ameliorates NASH in mice induced by a choline-deficient, amino acid-defined diet with 45% fat |
title_sort | pparα agonist and metformin co-treatment ameliorates nash in mice induced by a choline-deficient, amino acid-defined diet with 45% fat |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658250/ https://www.ncbi.nlm.nih.gov/pubmed/33177546 http://dx.doi.org/10.1038/s41598-020-75805-z |
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