TWEAK/Fn14 signaling is required for liver regeneration after partial hepatectomy in mice.
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BACKGROUND & AIMS: Pro-inflammatory cytokines are important for liver regeneration after partial hepatectomy (PH). Expression of Fibroblast growth factor-inducible 14 (Fn14), the receptor for TNF-like weak inducer of apoptosis (TWEAK), is induced rapidly after PH and remains elevated throughout the period of peak hepatocyte replication. The role of Fn14 in post-PH liver regeneration is uncertain because Fn14 is expressed by liver progenitors and TWEAK-Fn14 interactions stimulate progenitor growth, but replication of mature hepatocytes is thought to drive liver regeneration after PH. METHODS: To clarify the role of TWEAK-Fn14 after PH, we compared post-PH regenerative responses in wild type (WT) mice, Fn14 knockout (KO) mice, TWEAK KO mice, and WT mice treated with anti-TWEAK antibodies. RESULTS: In WT mice, rare Fn14(+) cells localized with other progenitor markers in peri-portal areas before PH. PH rapidly increased proliferation of Fn14(+) cells; hepatocytic cells that expressed Fn14 and other progenitor markers, such as Lgr5, progressively accumulated from 12-8 h post-PH and then declined to baseline by 96 h. When TWEAK/Fn14 signaling was disrupted, progenitor accumulation, induction of pro-regenerative cytokines, hepatocyte and cholangiocyte proliferation, and over-all survival were inhibited, while post-PH liver damage and bilirubin levels were increased. TWEAK stimulated proliferation and increased Lgr5 expression in cultured liver progenitors, but had no effect on either parameter in cultured primary hepatocytes. CONCLUSIONS: TWEAK-FN14 signaling is necessary for the healthy adult liver to regenerate normally after acute partial hepatectomy.
Mice, Inbred C57BL
Receptors, Tumor Necrosis Factor
Tumor Necrosis Factors
Published Version (Please cite this version)10.1371/journal.pone.0083987
Publication InfoBurkly, LC; Choi, SS; Diehl, Anna Mae; Garman, Katherine S; Karaca, G; Krüger, L; ... Xie, G (2014). TWEAK/Fn14 signaling is required for liver regeneration after partial hepatectomy in mice. PLoS One, 9(1). pp. e83987. 10.1371/journal.pone.0083987. Retrieved from https://hdl.handle.net/10161/11083.
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Florence McAlister Professor of Medicine
Our lab has a long standing interest in liver injury and repair. To learn more about the mechanisms that regulate this process, we study cultured cells, animal models of acute and chronic liver damage and samples from patients with various types of liver disease. Our group also conducts clinical trials in patients with chronic liver disease. We are particularly interested in fatty liver diseases, such as alcoholic fatty liver disease and nonalcoholic fatty liver disease (NAFLD). <br
Associate Professor of Medicine
My research focuses on injury, repair, and cancer development in the gastrointestinal tract. My laboratory performs translational research with the goal of improving health of the gastrointestinal tract. Our work is based in observations from human clinical research. We use databases of esophageal and colon disease to learn more about clinical risk factors for disease. We also use pathology samples of tumors to study the gastrointestinal tract in different states: healthy, inflamed or da
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