Here we show that hepatocyte-specific ablation of IKK2 in the context of disturbed bile homeostasis induced by Mdr2 deficiency results in severe cholestatic liver disease in young age, suggesting that activation of the IKK2/NF-κB pathway in hepatocytes constitutes an essential regulator of liver function under conditions of bile duct inflammation. The gene discussed is NFKB1; the disease is Cholestatic liver disease.