Universität zu Köln

Krishna-Subramanian, Santosh, Singer, Stephan, Armaka, Marietta, Banales, Jesus M., Holzer, Kerstin, Schirmacher, Peter, Walczak, Henning ORCID: 0000-0002-6312-4591, Kollias, George, Pasparakis, Manolis ORCID: 0000-0002-9870-0966 and Kondylis, Vangelis ORCID: 0000-0002-6970-8731 (2019). RIPK1 and death receptor signaling drive biliary damage and early liver tumorigenesis in mice with chronic hepatobiliary injury. Cell Death Differ., 26 (12). S. 2710 - 2727. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5403

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Abstract

Hepatocyte apoptosis is intrinsically linked to chronic liver disease and hepatocarcinogenesis. Conversely, necroptosis of hepatocytes and other liver cell types and its relevance for liver disease is debated. Using liver parenchymal cell (LPC)- specific TGF-beta-activated kinase 1 (TAK1)-deficient (TAK1(LPC-KO)) mice, which exhibit spontaneous hepatocellular and biliary damage, hepatitis, and early hepatocarcinogenesis, we have investigated the contribution of apoptosis and necroptosis in hepatocyte and cholangiocyte death and their impact on liver disease progression. Here, we provide in vivo evidence showing that TAK1-deficient cholangiocytes undergo spontaneous necroptosis induced primarily by TNFR1 and dependent on RIPK1 kinase activity, RIPK3, and NEMO. In contrast, TAK1-deficient hepatocytes die by FADD-dependent apoptosis, which is not significantly inhibited by LPC-specific RIPK1 deficiency, inhibition of RIPK1 kinase activity, RIPK3 deficiency or combined LPC-specific deletion of TNFR1, TRAILR, and Fas. Accordingly, normal mouse cholangiocytes can undergo necroptosis, while primary hepatocytes are resistant to it and die exclusively by apoptosis upon treatment with cell death-inducing stimuli in vitro, likely due to the differential expression of RIPK3. Interestingly, the genetic modifications that conferred protection from biliary damage also prevented the spontaneous lethality that was often observed in TAK1(LPC-KO) mice. In the presence of chronic hepatocyte apoptosis, preventing biliary damage delayed but did not avert hepatocarcinogenesis. On the contrary, inhibition of hepatocyte apoptosis fully prevented liver tumorigenesis even in mice with extensive biliary damage. Altogether, our results suggest that using RIPK1 kinase activity inhibitors could be therapeutically useful for cholestatic liver disease patients.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Krishna-Subramanian, Santosh UNSPECIFIED UNSPECIFIED UNSPECIFIED Singer, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Armaka, Marietta UNSPECIFIED UNSPECIFIED UNSPECIFIED Banales, Jesus M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Holzer, Kerstin UNSPECIFIED UNSPECIFIED UNSPECIFIED Schirmacher, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Walczak, Henning UNSPECIFIED orcid.org/0000-0002-6312-4591 UNSPECIFIED Kollias, George UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Kondylis, Vangelis UNSPECIFIED orcid.org/0000-0002-6970-8731 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-126503
DOI:	10.1038/s41418-019-0330-9
Journal or Publication Title:	Cell Death Differ.
Volume:	26
Number:	12
Page Range:	S. 2710 - 2727
Date:	2019
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5403
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; HEPATOCELLULAR-CARCINOMA; NEMO/IKK-GAMMA; PROTECTS MICE; CELL-DEATH; APOPTOSIS; HEPATOCYTES; NECROSIS; HEPATOCARCINOGENESIS; NECROPTOSIS Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12650