Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice

Abstract Growth differentiation factor 15 (GDF15) is an endocrine hormone belonging to the TGFβ superfamily member. GDF15 administration or GDF15 overexpression has been reported to have anti-obesity and anti-diabetic effects. Although non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohe...

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Autores principales: Kook Hwan Kim, Seong Hun Kim, Dai Hoon Han, Young Suk Jo, Yong-ho Lee, Myung-Shik Lee
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Publicado: Nature Portfolio 2018
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spelling oai:doaj.org-article:32eac4dcab774f319256f97ced562f952021-12-02T11:41:04ZGrowth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice10.1038/s41598-018-25098-02045-2322https://doaj.org/article/32eac4dcab774f319256f97ced562f952018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25098-0https://doaj.org/toc/2045-2322Abstract Growth differentiation factor 15 (GDF15) is an endocrine hormone belonging to the TGFβ superfamily member. GDF15 administration or GDF15 overexpression has been reported to have anti-obesity and anti-diabetic effects. Although non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is frequently associated with obesity and insulin resistance, the functional role of endogenous GDF15 and therapeutic effect of GDF15 overexpression in NASH and related metabolic deterioration have not been evaluated. Here, we found that GDF15 expression was increased in the livers of NASH animal models and human subjects with NASH. Elevated expression of GDF15 was due to diet-induced hepatic endoplasmic reticulum (ER) stress. Gdf15-knockout mice exhibited aggravated NASH phenotypes such as increased steatosis, hepatic inflammation, fibrosis, liver injury, and metabolic deterioration. Furthermore, GDF15 directly suppressed expression of fibrosis-related genes and osteopontin (OPN), contributing factors for NASH-related fibrosis, in hepatic stellate cells in vitro and in the liver of mice in vivo. Finally, we found that GDF15-transgenic mice showed attenuation of NASH phenotypes and metabolic deterioration. Therefore, our results suggest that induction of endogenous GDF15 is a compensatory mechanism to protect against the progression of NASH and that GDF15 could be an attractive therapeutic candidate for treatment of NASH and NASH-related metabolic deterioration.Kook Hwan KimSeong Hun KimDai Hoon HanYoung Suk JoYong-ho LeeMyung-Shik LeeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-14 (2018)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Kook Hwan Kim
Seong Hun Kim
Dai Hoon Han
Young Suk Jo
Yong-ho Lee
Myung-Shik Lee
Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice
description Abstract Growth differentiation factor 15 (GDF15) is an endocrine hormone belonging to the TGFβ superfamily member. GDF15 administration or GDF15 overexpression has been reported to have anti-obesity and anti-diabetic effects. Although non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is frequently associated with obesity and insulin resistance, the functional role of endogenous GDF15 and therapeutic effect of GDF15 overexpression in NASH and related metabolic deterioration have not been evaluated. Here, we found that GDF15 expression was increased in the livers of NASH animal models and human subjects with NASH. Elevated expression of GDF15 was due to diet-induced hepatic endoplasmic reticulum (ER) stress. Gdf15-knockout mice exhibited aggravated NASH phenotypes such as increased steatosis, hepatic inflammation, fibrosis, liver injury, and metabolic deterioration. Furthermore, GDF15 directly suppressed expression of fibrosis-related genes and osteopontin (OPN), contributing factors for NASH-related fibrosis, in hepatic stellate cells in vitro and in the liver of mice in vivo. Finally, we found that GDF15-transgenic mice showed attenuation of NASH phenotypes and metabolic deterioration. Therefore, our results suggest that induction of endogenous GDF15 is a compensatory mechanism to protect against the progression of NASH and that GDF15 could be an attractive therapeutic candidate for treatment of NASH and NASH-related metabolic deterioration.
format article
author Kook Hwan Kim
Seong Hun Kim
Dai Hoon Han
Young Suk Jo
Yong-ho Lee
Myung-Shik Lee
author_facet Kook Hwan Kim
Seong Hun Kim
Dai Hoon Han
Young Suk Jo
Yong-ho Lee
Myung-Shik Lee
author_sort Kook Hwan Kim
title Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice
title_short Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice
title_full Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice
title_fullStr Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice
title_full_unstemmed Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice
title_sort growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice
publisher Nature Portfolio
publishDate 2018
url https://doaj.org/article/32eac4dcab774f319256f97ced562f95
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