Format

Send to

Choose Destination
Sci Rep. 2017 Dec 8;7(1):17238. doi: 10.1038/s41598-017-17574-w.

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

Chung HK1,2, Kim JT1,3, Kim HW1,3, Kwon M1, Kim SY4, Shong M1,5, Kim KS6,7, Yi HS8,9.

Author information

1
Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon, 35015, Republic of Korea.
2
Research Institute for Medical Sciences, Chungnam National University School of Medicine, 266 Munhwaro, Daejeon, 35015, Republic of Korea.
3
Department of Medical Science, Chungnam National University School of Medicine, 266 Munhwaro, Daejeon, 35015, Republic of Korea.
4
Laboratory of Liver Research, Biomedical Science and Engineering Interdisciplinary program, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea.
5
Department of Internal Medicine, Chungnam National University Hospital, 282 Munhwaro, Daejeon, 35015, Republic of Korea.
6
Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon, 35015, Republic of Korea. kunsunkim@cnu.ac.kr.
7
Department of Medical Science, Chungnam National University School of Medicine, 266 Munhwaro, Daejeon, 35015, Republic of Korea. kunsunkim@cnu.ac.kr.
8
Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, 282 Munhwaro, Daejeon, 35015, Republic of Korea. jmpbooks@cnuh.co.kr.
9
Department of Internal Medicine, Chungnam National University Hospital, 282 Munhwaro, Daejeon, 35015, Republic of Korea. jmpbooks@cnuh.co.kr.

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center