RRC ID 52692
Author Kim KH, Kim SH, Han DH, Jo YS, Lee YH, Lee MS.
Title Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice.
Journal Sci Rep
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.
Volume 8(1)
Pages 6789
Published 2018-5-1
DOI 10.1038/s41598-018-25098-0
PII 10.1038/s41598-018-25098-0
PMID 29717162
PMC PMC5931608
MeSH Actins / genetics Actins / metabolism Animals Choline Deficiency / genetics* Choline Deficiency / metabolism Choline Deficiency / pathology Collagen Type I / genetics Collagen Type I / metabolism Collagen Type I, alpha 1 Chain Diet / adverse effects Disease Models, Animal Endoplasmic Reticulum Stress / genetics* Gene Expression Regulation Growth Differentiation Factor 15 / deficiency Growth Differentiation Factor 15 / genetics* Hepatic Stellate Cells / metabolism* Hepatic Stellate Cells / pathology Humans Liver / metabolism* Liver / pathology Liver Cirrhosis / etiology Liver Cirrhosis / genetics* Liver Cirrhosis / metabolism Liver Cirrhosis / pathology Male Methionine / deficiency Mice Mice, Inbred C57BL Mice, Knockout Non-alcoholic Fatty Liver Disease / etiology Non-alcoholic Fatty Liver Disease / genetics* Non-alcoholic Fatty Liver Disease / metabolism Non-alcoholic Fatty Liver Disease / pathology Osteopontin / genetics Osteopontin / metabolism Primary Cell Culture Signal Transduction Tissue Inhibitor of Metalloproteinase-1 / genetics Tissue Inhibitor of Metalloproteinase-1 / metabolism Transcription Factor CHOP / genetics Transcription Factor CHOP / metabolism Transforming Growth Factor beta1 / genetics Transforming Growth Factor beta1 / metabolism
IF 3.998
Times Cited 22
Human and Animal Cells KUP5(RCB4627)