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 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.

Selective Liver Estrogen Receptor α Modulation Prevents Steatosis, Diabetes, and Obesity Through the Anorectic Growth Differentiation Factor 15 Hepatokine in Mice

“…(40) Moreover, GDF15KO mice are also prone to develop steatosis, while GDF15-transgenic mice are protected from steatosis and associated metabolic disorders. (41) Finally, in agreement with our results, prevention of obesity in HFD-fed mice treated with recombinant GDF15 was not associated with an increase in energy expenditure, suggesting that the protective action of this hepatokine is likely driven by the reduction in food intake. (36) These considerations prompted us to directly address the role of Gdf15 in whole-body metabolic protective TAM effects.…”

“…Accordingly, GDF15KO mice are characterized by accelerated weight gain and increased fat mass, mainly localized in visceral abdominal sites, but their food intake and body weight returned to the WT level following infusion with recombinant human GDF15 . Moreover, GDF15KO mice are also prone to develop steatosis, while GDF15 ‐transgenic mice are protected from steatosis and associated metabolic disorders . Finally, in agreement with our results, prevention of obesity in HFD‐fed mice treated with recombinant GDF15 was not associated with an increase in energy expenditure, suggesting that the protective action of this hepatokine is likely driven by the reduction in food intake .…”

“…However, this lack of demonstration of the cellular sources of Gdf15 in the liver of TAM‐treated mice does not challenge our main conclusion, i.e., the specific regulation of liver Gdf15 by TAM requires ERα activation in hepatocytes. GDF15 expression levels are physiologically low but rapidly increase in pathophysiological conditions, such as tissue injury, inflammation, and malignancy, as well as during dysmetabolic status, including obesity, type 2 diabetes, and NAFLD . Interestingly, our study demonstrates that hepatocyte ERα is also able to enhance Gdf15 expression according to its mode of activation.…”

“…GDF15 expression levels are physiologically low but rapidly increase in pathophysiological conditions, such as tissue injury, inflammation, and malignancy, as well as during dysmetabolic status, including obesity, type 2 diabetes, and NAFLD. (41) Interestingly, our study demonstrates that hepatocyte ERα is also able to enhance Gdf15 expression according to its mode of activation. Contrasting with the significant increase induced by TAM, Gdf15 liver expression and Gdf15 circulating levels were not altered by E2 chronic treatment.…”

β-arrestin: Dr Jekyll and Mr Hyde in NASH and fibrosis

“…[15][16][17] Another study in Gdf15-knockout and transgenic mice reported that GDF15 contributes to the improvement of liver fibrosis in the methioninecholine deficient (MCD) and the high fat/fructose/cholesterol (amylin) NASH models. 2,18 However, it is unclear whether this effect was due to weight loss or to direct anti-inflammatory and antifibrotic actions.…”