GDF15 deficiency exacerbates chronic alcohol- and carbon tetrachloride-induced liver injury

Abstract

Growth differentiation factor 15 (GDF15) has recently been shown to have an important role in the regulation of mitochondrial function and in the pathogenesis of complex human diseases. Nevertheless, the role of GDF15 in alcohol-induced or fibrotic liver diseases has yet to be determined. In this study, we demonstrate that alcohol- or carbon tetrachloride (CCl4)-mediated hepatic GDF15 production ameliorates liver inflammation and fibrosis. Alcohol directly enhanced GDF15 expression in primary hepatocytes, which led to increased oxygen consumption. Moreover, GDF15 reduced the expression of pro-inflammatory cytokines in liver-resident macrophages, leading to an improvement in inflammation and fibrosis in the liver. GDF15 knockout (KO) mice had more TNF-α-producing T cells and more activated CD4+ and CD8+ T cells in the liver than wild-type mice. Liver-infiltrating monocytes and neutrophils were also increased in the GDF15 KO mice during liver fibrogenesis. These changes in hepatic immune cells were associated with increased tissue inflammation and fibrosis. Finally, recombinant GDF15 decreased the expression of pro-inflammatory cytokines and fibrotic mediators and prevented the activation of T cells in the livers of mice with CCl4-induced liver fibrosis. These results suggest that GDF15 could be a potential therapeutic target for the treatment of alcohol-induced and fibrotic liver diseases.

CXCL5-mediated recruitment of neutrophils into the peritoneal cavity ofGdf15-deficient mice protects against abdominal sepsis

“…In this model, mice had a worse outcome as the excess number of neutrophils exacerbated the myocardial lesion (16). An excess recruitment of neutrophils has also been observed in Gdf15 -/mice in a model of CCl4-induced liver fibrogenesis (17), which contributed to lesion exacerbation. In contrast, in the present case of the CLP model the increased number of neutrophils lead to the better early control of the local infection.…”

An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models

“…Redox signalling is also involved in activation of the UPR mt , which increases lifespan and preserves mitochondrial function in D. melanogaster. Although there is presently no evidence for a role of the UPR mt in longevity or metabolic diseases in mammals, mitokines such as FGF21 and GDF15 are not only useful diagnostic biomarkers for human mitochondrial diseases, but are also a potential therapeutic modality for metabolic diseases [18,35,36,38,39]. Moreover, Fgf21 −/− and Gdf15 −/− mice are prone to HFD -induced obesity, glucose intolerance, and hepatic and adipose inflammation [40,41], suggesting an important role for these mitokines in whole-body metabolic homeostasis.…”

The MIC-1/GDF15-GFRAL Pathway in Energy Homeostasis: Implications for Obesity, Cachexia, and Other Associated Diseases

“…Both alcohol and carbon tetrachloride are hepatotoxins that induce acute and chronic liver injury and, in the case of the latter, can lead to fibrosis. While a single dose of carbon tetrachloride did not differentially impact liver injury in MIC-1/GDF15 KO mice (Hsiao et al, 2000), when administered over a more prolonged period, KO mice were much more susceptible to both alcohol-and carbon tetrachloride-mediated effects (Chung et al, 2017a). KO mice displayed increased levels of serum markers of liver injury, higher serum levels of TNF-a and IL6, and increased inflammatory changes within liver tissue.…”