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

 Kook Hwan Kim  ;  Seong Hun Kim  ;  Dai Hoon Han  ;  Young Suk Jo  ;  Yong-Ho Lee  ;  Myung-Shik Lee 
 Scientific Reports, Vol.8(1) : 6789, 2018 
Journal Title
 Scientific Reports 
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Growth differentiation factor 15 (GDF15) is an endocrine hormone belonging to the TGFbeta 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.
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1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실)
Yonsei Authors
김국환(Kim, Kook Hwan)
이명식(Lee, Myung Shik) ORCID logo https://orcid.org/0000-0003-3292-1720
이용호(Lee, Yong Ho) ORCID logo https://orcid.org/0000-0002-6219-4942
조영석(Jo, Young Suk) ORCID logo https://orcid.org/0000-0001-9926-8389
한대훈(Han, Dai Hoon) ORCID logo https://orcid.org/0000-0003-2787-7876
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