Growth differentiation factor 15 alleviates non-alcoholic steatohepatitis through anti-inflammatory effect on intrahepatic macrophages

Abstract

Nonalcoholic steatohepatitis (NASH) is the advanced stage of nonalcoholic fatty liver disease (NAFLD) and is characterized by lipid accumulation, hepatocellular injury, hepatocyte degeneration, hepatic inflammation, and different stages of fibrosis. People with NASH are at high risk of developing liver fibrosis, cirrhosis and even liver cancer. However, no NASH-specific drugs have been approved to date by the US Food and Drug Administration (FDA).

Growth differentiation factor (GDF) 15 is a divergent member of the transforming growth factor-β (TGF-β) superfamily and is well known as a stress-induced cytokine correlated with cancer, cardiovascular disease, acute liver injury, chronic liver diseases and chronic kidney diseases. Circulating GDF15 forms a complex with its receptor, GDNF receptor α like (GFRAL), and its co-receptor, proto-oncogene tyrosine-protein kinase receptor (RET) and then activates neurons within the area postrema (AP) and nucleus of the solitary tract (NTS) to inhibit appetite and promote body weight loss.

A clinical study reported induction of GDF15 in Korean NAFLD patients and proposed GDF15 as an independent predictor of liver fibrosis but not for other stages of NAFLD. The association of GDF15 with NASH especially in Chinese patients remains obscure and the role of GDF15 in the development of NASH has not yet been clearly identified. Therefore, our study aims to investigate the following: 1) whether GDF15 is associated with the progression of NASH; 2) what the source of GDF15 induction is under NASH; 3) whether GDF15 plays a role in the development of NASH; 4) the mechanism underlying the action of GDF15 in NASH; and 5) whether GDF15 can be a potential therapeutic target in treatment of NASH.

Our study shows that GDF15 levels are stepwisely increased during the development of NASH in a Chinese obese cohort and are positively associated with liver injury markers as well as hepatic lipid content. Serum GDD15 is also an independent risk factor for developing NASH in human. Furthermore, hepatocyte derived GDF15 contributes to the elevated serum GDF15 levels during NASH in mice.

GDF15 deficiency exacerbates hepatic inflammation and liver fibrosis while recombinant GDF15 treatment alleviates hepatic inflammation as well as fibrosis. These results indicate a protective role of GDF15 in the development of NASH and the potential of GDF15 as a therapeutic target for NASH.

The present study further reveals that hepatic macrophages are the target cells for the beneficial effect of GDF15 in NASH. GDF15 decreases the expression of pro-inflammatory cytokines in macrophages both in-vivo and in-vitro. The inhibition of the STAT3 pathway in macrophages may have mediated the anti-inflammatory effect of GDF15.

Collectively, the findings in our study demonstrate the clinical value of GDF15 as a novel biomarker of NASH and indicate the beneficial role of GDF15 in the development of NASH through its anti-inflammatory effect on hepatic macrophages.