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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide[1]
non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) has been reported to be frequently associated with obesity or insulin resistance, to the best of our knowledge, the functional importance of Growth differentiation factor 15 (GDF15) in NASH and related metabolic disorders has not been evaluated
Mice with deletion of Gdf[15] showed aggravated metabolic parameters such as increased body weight and elevated fasting glucose or insulin level after Amylin liver NASH (AMLN) diet feeding. These results suggest that endogenous GDF15 plays a crucial role in attenuating NASH and NASH-related metabolic deterioration in mice
Summary
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide[1]. Simple steatosis can lead to the development of NASH accompanied by inflammation or fibrosis through multiple events including insulin resistance, oxidative stress, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, adipose tissue dysfunction, altered regulation of innate immunity or compositional changes of microbiota[4] Based on these findings, the “multi-parallel hit” hypothesis has been recently proposed to explain the pathogenesis of NASH. We showed aggravated hepatic steatosis, inflammation, fibrosis and metabolic deterioration in Gdf15-knockout (Gdf15−/−) mice fed two different NASH diets, while these pathologic and metabolic features were attenuated in GDF15-transgenic (GDF15-Tg) mice These results suggest that GDF15 is induced in the liver as a compensatory mechanism to protect against NASH and related metabolic disorders
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