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

Hyo Kyun Chung,Koon Soon Kim,Minho Shong,Hyon-Seung Yi,Hyeon-Woo Kim,Jung Tae Kim,So Yeon Kim,Minjoo Kwon

doi:10.1038/s41598-017-17574-w

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.

Highlights

The liver can be considered an immunologic organ, in which antigen-rich blood from the gastrointestinal tract interacts with diverse innate and adaptive immune cells[1,2]
Based on previous observations that Growth differentiation factor 15 (GDF15) expression is associated with the mitochondrial stress response, we examined the effect of alcohol on GDF15 expression in hepatocytes and non-parenchymal cells
We investigated the effect of mitochondrial dysfunction on GDF15 expression in hepatocytes

Summary

Introduction

The liver can be considered an immunologic organ, in which antigen-rich blood from the gastrointestinal tract interacts with diverse innate and adaptive immune cells[1,2] These immune cells play important roles in the development of hepatic inflammation, steatohepatitis, and fibrotic liver diseases[3,4]. The radicals produced by cytochrome P450 2E1-mediated CCl4 metabolism bind to mtDNA directly and promote lipid peroxidation, which results in degradation of mtDNA20,21. Hepatotoxic molecules such as alcohol and CCl4 promote mitochondrial dysfunction in the liver, the role of GDF15 as a mitohormetic factor in alcohol- and CCl4-induced liver injury remains to be elucidated. This study provides a range of pathophysiological insights into alcoholic and fibrotic liver diseases

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Results

Conclusion