Disruption of TAK1 in hepatocytes causes hepatic injury, inflammation, fibrosis, and carcinogenesis

Abstract

TGF-β–activated kinase 1 (TAK1) is a MAP3K family member that activates NF-κB and JNK via Toll-like receptors and the receptors for IL-1, TNF-α, and TGF-β. Because the TAK1 downstream molecules NF-κB and JNK have opposite effects on cell death and carcinogenesis, the role of TAK1 in the liver is unpredictable. To address this issue, we generated hepatocyte-specific Tak1 -deficient ( Tak1ΔHEP ) mice. The Tak1ΔHEP mice displayed spontaneous hepatocyte death, compensatory proliferation, inflammatory cell infiltration, and perisinusoidal fibrosis at age 1 month. Older Tak1ΔHEP mice developed multiple cancer nodules characterized by increased expression of fetal liver genes including α-fetoprotein. Cultures of primary hepatocytes deficient in Tak1 exhibited spontaneous cell death that was further increased in response to TNF-α. TNF-α increased caspase-3 activity but activated neither NF-κB nor JNK in Tak1 -deficient hepatocytes. Genetic abrogation of TNF receptor type I (TNFRI) in Tak1ΔHEP mice reduced liver damage, inflammation, and fibrosis compared with unmodified Tak1ΔHEP mice. In conclusion, hepatocyte-specific deletion of TAK1 in mice resulted in spontaneous hepatocyte death, inflammation, fibrosis, and carcinogenesis that was partially mediated by TNFR signaling, indicating that TAK1 is an essential component for cellular homeostasis in the liver.

TAK1 control of cell death

“…Nonetheless, these tissue injuries are associated with caspase activation and are not rescued by Ripk3 deletion, indicating that they are primarily apoptosis. 37,49,55,57,[82][83][84][85]88 We note here that the role of TAK1 in vivo may not be limited to prevention of cell death. For example, Tak1-deficient neutrophils hyperproliferate rather than dying spontaneously, leading to splenomegaly and myelomonocytic leukemia.…”

“…37 Hepatocyte-specific deletion of Tak1 also causes cell death and liver injury. 57,83 However, unlike epithelial and endothelial tissues, Tak1 deficiency in hepatocytes does not cause profound tissue damage and is not associated with immediate animal mortality. Instead, Tak1-deficient hepatocyte death induces inflammation and promotes compensatory proliferation, which eventually leads to hepatocellular carcinoma within 6 weeks.…”

“…Instead, Tak1-deficient hepatocyte death induces inflammation and promotes compensatory proliferation, which eventually leads to hepatocellular carcinoma within 6 weeks. 57,83 Hematopoietic-specific Tak1 deletion depletes hematopoietic progenitor cells, T cells and macrophages. [10][11][12]58,[84][85][86][87] Deletion of TNF receptor 1 (Tnfr1) largely rescues these injuries and animal mortalities, 37,55,57,[82][83][84][85] demonstrating that TNFa is the major killer of Tak1-deficient cells in these tissues.…”

“…Lethal E10-11 8,25,119 (Epidermis) Increased cell death-4Lethal P5-7 82 (Intestinal epithelium) Increased cell death-4Lethal P0 55 (Inducible intestinal epithelium) Ileitis and loss of paneth cells 55,65 (Endothelium/blood vessel) Increased cell death, defective vascularization-4Lethal E10-11 37 (Liver) Increased cell death-4Hepatocellular carcinoma within 6 weeks of age 57,83 (Hematopoietic system) Increased cell death-4Depletion of stem cells [84][85][86] (Myeloid) Macrophage death, splenomegaly and hyperproliferation of neutrophils 87,89 Tab1 Lethal E15-16 120 There is a well-studied inhibitory regulation from apoptosis to necroptosis (Figure 4, blue inhibition arrow). Thus, inhibition of caspase-8 activates necroptosis.…”

TNFR1 determines progression of chronic liver injury in the IKKγ/Nemo genetic model

“…30,31 TNFR1 also contributes to spontaneous liver injury, inflammation and fibrosis in hepatocyte-specific TAK1 knockout mice. 32 Previous publications 33 suggest that LPS via the activation of TLR4 and the downregulation of BAMBI is profibrogenic, which could also explain the reduced fibrogenesis in Nemo Dhepa /TNFR1 livers.…”