Deletion of NEMO/IKKγ in Liver Parenchymal Cells Causes Steatohepatitis and Hepatocellular Carcinoma

Abstract

The IkappaB kinase (IKK) subunit NEMO/IKKgamma is essential for activation of the transcription factor NF-kappaB, which regulates cellular responses to inflammation. The function of NEMO in the adult liver remains elusive. Here we show that ablation of NEMO in liver parenchymal cells caused the spontaneous development of hepatocellular carcinoma in mice. Tumor development was preceded by chronic liver disease resembling human nonalcoholic steatohepatitis (NASH). Antioxidant treatment and genetic ablation of FADD demonstrated that death receptor-mediated and oxidative stress-dependent death of NEMO-deficient hepatocytes triggered disease pathogenesis in this model. These results reveal that NEMO-mediated NF-kappaB activation in hepatocytes has an essential physiological function to prevent the spontaneous development of steatohepatitis and hepatocellular carcinoma, identifying NEMO as a tumor suppressor in the liver.

The unexpected role of lymphotoxin β receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development

“…In this model, spontaneous HCC development is preceded by steatohepatitis, increased hepatocyte apoptosis and compensatory liver regeneration. These findings suggest that NF-kB has an active role in protecting the liver from cancer and emphasizes the role of NEMO/IKKg as a tumor suppressor (Luedde et al, 2007). Of note, it was described that the MAP3-kinase TGF-b-activated kinase 1 (TAK1) suppresses a NEMO-dependent but NF-kB-independent pathway to liver cancer (Bettermann et al, 2010).…”

“…Ablation of NEMO/IKKg in hepatocytes results in the development of steatohepatitis and HCC (Luedde et al, 2007). In this model, spontaneous HCC development is preceded by steatohepatitis, increased hepatocyte apoptosis and compensatory liver regeneration.…”

Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

“…FADD is essential for the recruitment and activation of caspase-8 and the induction of apoptosis downstream of death receptors including TNFR1, Fas and TRAIL-R. We showed previously that LPC-specific FADD deficiency strongly reduced early hepatitis in NEMO LPC-KO mice as indicated by significantly lower serum alanine aminotransferase (ALT) levels and reduced hepatocyte apoptosis and compensatory proliferation. 15 To further characterize the role of FADD in the spontaneous development of hepatitis and HCC in NEMO LPC-KO mice, we analysed groups of NEMO LPC-KO /FADD LPC-KO mice at the age of 8 weeks or 1 year. NEMO LPC-KO /FADD LPC-KO mice had average serum ALT levels of about 200 U/l, which were significantly reduced compared with NEMO LPC-KO mice but higher than the background levels of wild-type control mice, indicating that FADD deficiency did not fully prevent liver damage in NEMO LPC-KO mice ( Figure 1a).…”

“…NEMO LPC-KO mice showed spontaneous hepatocyte apoptosis resulting in chronic steatohepatitis and the development of HCC by the age of 1 year. 15 LPC-specific ablation of Fas-Associated with Death Domain (FADD or MORT1), an adapter protein essential for the recruitment of caspase-8 to the Death Inducing Signalling Complex and the induction of death receptor-mediated apoptosis, 16 prevented both spontaneous and LPS-induced apoptosis of NEMO-deficient hepatocytes and the development of steatohepatitis. 15 In addition, LPCspecific knockout of caspase-8 inhibited spontaneous hepatocyte apoptosis and HCC development in NEMO LPC-KO mice, although it caused non-apoptotic hepatocyte death and cholestasis.…”

“…15 LPC-specific ablation of Fas-Associated with Death Domain (FADD or MORT1), an adapter protein essential for the recruitment of caspase-8 to the Death Inducing Signalling Complex and the induction of death receptor-mediated apoptosis, 16 prevented both spontaneous and LPS-induced apoptosis of NEMO-deficient hepatocytes and the development of steatohepatitis. 15 In addition, LPCspecific knockout of caspase-8 inhibited spontaneous hepatocyte apoptosis and HCC development in NEMO LPC-KO mice, although it caused non-apoptotic hepatocyte death and cholestasis. 17 Given the essential role of FADD and caspase-8 in mediating apoptosis downstream of death receptors, 16 we hypothesized that death receptor-mediated apoptosis of NEMO-deficient hepatocytes drives the development of hepatitis and HCC in NEMO LPC-KO mice.…”