Growth Differentiation Factor 15 Ameliorates Nonalcoholic Steatohepatitis Associated with Metabolic Syndrome in Mice

Growth differentiation factor 15 (GDF15) is an endocrine hormone belonging TGFβ superfamily member. GDF15 administration or GDF15 overexpression has been reported to have anti-obesity and antidiabetic effects. Although nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is frequently associated with metabolic syndrome or diabetes, the functional role of endogenous GDF15 and therapeutic effect of exogenous GDF15 in NASH associated metabolic syndrome have not been addressed. We studied whether GDF15 has therapeutic effects on NASH and associated metabolic syndrome.

To this end, Gdf15-knockout and Gdf15-transgenic mice were employed, and mice were fed Amylin liver NASH (AMLN) diet as a physiologically relevant dietary mouse model of NASH associated with metabolic syndrome.

GDF15 expression was increased in the livers of mice fed AMLN diet and human subjects with NASH. Elevated expression of GDF15 was due to diet-induced endoplasmic reticulum (ER) stress in the liver. Importantly, Gdf15-knockout mice exhibited deteriorated metabolic syndrome and aggravated NASH phenotypes such as increased steatosis, hepatic inflammation, fibrosis and liver injury. Furthermore, we found that GDF15 directly suppresses expression of fibrosis-related genes and osteopontin (OPN) in the liver in vivo. OPN expression was increased in hepatocytes and stellate cells in the liver of Gdf15-knockout mice. Finally, we found that GDF15-transgenic mice showed attenuated NASH phenotypes and improved glucose tolerance in mice fed AMLN diet. Our results suggest that induction of endogenous GDF15 is a compensatory mechanism to protect against NASH associated with metabolic syndrome and that GDF15 could be an attractive therapeutic candidate for treatment of these diseases.