NF-κB reactivation in TAK1LPC-KO mice induces lethal cholemic nephropathy

Hepatocellular carcinoma (HCC), the common end-stage of chronic liver diseases, arises almost exclusively in the context of chronic hepatic inflammation. The transcription factor NF-κB serves as an important regulator of these inflammatory processes, although its role in hepatocarcinogenesis remains controversial. Conditional deletion of TAK1 (TGF-β-Activated-Kinase-1) in liver parenchymal cells (LPC; TAK1LPC-KO) in mice is characterized by the inactivation of NF-κB and concomitant activation of spontaneous hepatocyte apoptosis and cholangiocyte necroptosis. This activation of spontaneous cell death leads to cholestasis, liver inflammation, liver regeneration and eventually drives hepatocarcinogenesis. While apoptosis and necroptosis exert differential effects on cholestasis and hepatocarcinogenesis in TAK1LPC-KO mice, the impact of inactivated NF-κB signaling on disease progression remains unclear.

To investigate the impact of reactivating NF-κB signaling in TAK1LPC-KO mice, we genetically expressed a constitutively active form of the NF-κB-inducing kinase IKK2 (IKK2ca) with TAK1LPC-KO mice (TAK1LPC-KO/IKK2LPC-ca). NF-κB reactivation in TAK1LPC-KO mice abolished hepatocyte apoptosis and, consequently, prevented the strong compensatory cell proliferation and concomitant hepatocarcinogenesis. In contrast, hepatic NF-κB reactivation was unable to prevent cholangiocyte necroptosis, and in fact, it exacerbated the observed ductopenia. This is probably also due to the loss of compensatory proliferation by inhibiting apoptosis. Despite a robust transdifferentiation of hepatocytes into Sox9-positive progenitors, mature bile ducts could not be restored, resulting in lethal cholemic nephropathy.

Publication History

Article published online:
20 January 2025