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Hepatocyte-Specific TAK1 Deficiency Drives RIPK1 Kinase-dependent Inflammation to Promote Liver Fibrosis and Hepatocellular Carcinoma

ABSTRACT: Transforming growth factor beta-activated kinase1 (TAK1) encoded by the gene MAP3K7 regulates multiple important downstream effectors involved in immune response, cell death and carcinogenesis. Hepatocyte-specific deletion of TAK1 in Tak1_Hep mice promotes liver fibrosis and hepatocellular carcinoma (HCC) formation. Here, we report that genetic inactivation of RIPK1 kinase using kinase dead knock-in D138N mutation in Tak1_Hep mice inhibits the expression of liver tumor biomarkers, liver fibrosis and HCC formation. Inhibition of RIPK1, however, has no or minimum effect on hepatocyte loss and compensatory proliferation, which are the recognized factors important for liver fibrosis and HCC development. Using single cell RNA-seq, we discover that inhibition of RIPK1 strongly suppresses inflammation induced by hepatocyte-specific loss of TAK1. Activation of RIPK1 promotes the transcription of key proinflammatory cytokines, such as CCL2, and CCR2+ macrophage infiltration. Our study demonstrates the role and mechanism of RIPK1 kinase in promoting inflammation, both cell-autonomously and cell-non-autonomously, in the development of liver fibrosis and HCC, independent of cell death and compensatory proliferation. We suggest the possibility of inhibiting RIPK1 kinase as a therapeutic strategy for reducing liver fibrosis and HCC development by inhibiting inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE148859 | GEO | 2020/07/08

REPOSITORIES: GEO

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Hepatocyte-Specific TAK1 Deficiency Drives RIPK1 Kinase-dependent Inflammation to Promote Liver Fibrosis and Hepatocellular Carcinoma

Project description:Hepatocyte-Specific TAK1 Deficiency Drives RIPK1 Kinase-dependent Inflammation to Promote Liver Fibrosis and Hepatocellular Carcinoma

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TBK1 suppresses RIPK1-driven apoptosis and inflammation during development and in aging

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The Stress-Regulated Transcription Factor CHOP Promotes Hepatic Inflammatory Gene Expression, Fibrosis, and Oncogenesis

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2013-09-27 | E-GEOD-51188 | biostudies-arrayexpress

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Protein Kinase / suppresses liver cancer by repressing autophagy and oxidative phosphorylation in hepatocytes [DH]

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2020-06-30 | GSE147800 | GEO

Protein Kinase / suppresses liver cancer by repressing autophagy and oxidative phosphorylation in hepatocytes [RD]

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2020-06-30 | GSE147778 | GEO

PR-SET7 inactivation causes hepatocyte necrosis and spontaneous development of hepatocellular carcinoma derived from ductal progenitor cells

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