A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) represents the most common liver disease in Western countries and often progresses to non-alcoholic steatohepatitis (NASH) leading ultimately to liver fibrosis and liver cancer. The occurrence of hepatocyte cell deathso far characterized as hepatocyte apoptosisrepresents a fundamental step from benign steatosis toward progressive steatohepatitis. In contrast, the function of RIP3-dependent necroptosis in NASH and NASH-induced fibrosis is currently unknown. We show that RIP3 is upregulated in human NASH and in a dietary mouse model of steatohepatitis. RIP3 mediates liver injury, inflammation, induction of hepatic progenitor cells/activated cholangiocytes, and liver fibrosis through a pathway suppressed by Caspase-8. This function of RIP3 is mediated by a positive feedback loop involving activation of Jun-(N)-terminal Kinase (JNK). Furthermore, RIP3-dependent JNK activation promotes the release of pro-inflammatory mediators like MCP-1, thereby attracting macrophages to the injured liver and further augmenting RIP3-dependent signaling, cell death, and liver fibrosis. Thus, RIP3-dependent necroptosis controls NASH-induced liver fibrosis. This pathway might represent a novel and specific target for pharmacological strategies in patients with NASH

RIP3 inhibits inflammatory hepatocarcinogenesis but promotes cholestasis by controlling caspase-8- and JNK-dependent compensatory cell proliferation

For years, the term "apoptosis" was used synonymously with programmed cell death. However, it was recently discovered that receptor interacting protein 3 (RIP3)-dependent "necroptosis" represents an alternative programmed cell death pathway activated in many inflamed tissues. Here, we show in a genetic model of chronic hepatic inflammation that activation of RIP3 limits immune responses and compensatory proliferation of liver parenchymal cells (LPC) by inhibiting Caspase-8-dependent activation of Jun-(N)-terminal kinase in LPC and nonparenchymal liver cells. In this way, RIP3 inhibits intrahepatic tumor growth and impedes the Caspase-8-dependent establishment of specific chromosomal aberrations that mediate resistance to tumor-necrosis-factor-induced apoptosis and underlie hepatocarcinogenesis. Moreover, RIP3 promotes the development of jaundice and cholestasis, because its activation suppresses compensatory proliferation of cholangiocytes and hepatic stem cells. These findings demonstrate a function of RIP3 in regulating carcinogenesis and cholestasis. Controlling RIP3 or Caspase-8 might represent a chemopreventive or therapeutic strategy against hepatocellular carcinoma and biliary disease

I kappa B Kinase alpha/beta Control Biliary Homeostasis and Hepatocarcinogenesis in Mice by Phosphorylating the Cell-Death Mediator Receptor-Interacting Protein Kinase 1

The I?B-Kinase (IKK) complex-consisting of the catalytic subunits, IKK? and IKK?, as well as the regulatory subunit, NEMO-mediates activation of the nuclear factor ?B (NF-?B) pathway, but previous studies suggested the existence of NF-?B-independent functions of IKK subunits with potential impact on liver physiology and disease. Programmed cell death is a crucial factor in the progression of liver diseases, and receptor-interacting kinases (RIPKs) exerts strategic control over multiple pathways involved in regulating novel programmed cell-death pathways and inflammation. We hypothesized that RIPKs might be unrecognized targets of the catalytic IKK-complex subunits, thereby regulating hepatocarcinogenesis and cholestasis. In this present study, mice with specific genetic inhibition of catalytic IKK activity in liver parenchymal cells (LPCs; IKK?/?(LPC-KO) ) were intercrossed with RIPK1(LPC-KO) or RIPK3(-/-) mice to examine whether RIPK1 or RIPK3 might be downstream targets of IKKs. Moreover, we performed in vivo phospho-proteome analyses and in vitro kinase assays, mass spectrometry, and mutagenesis experiments. These analyses revealed that IKK? and IKK?-in addition to their known function in NF-?B activation-directly phosphorylate RIPK1 at distinct regions of the protein, thereby regulating cell viability. Loss of this IKK?/?-dependent RIPK1 phosphorylation in LPCs inhibits compensatory proliferation of hepatocytes and intrahepatic biliary cells, thus impeding HCC development, but promoting biliary cell paucity and lethal cholestasis.IKK-complex subunits transmit a previously unrecognized signal through RIPK1, which is fundamental for the long-term consequences of chronic hepatic inflammation and might have potential implications for future pharmacological strategies against cholestatic liver disease and cancer. (Hepatology 2016;64:1217-1231).? 2016 by the American Association for the Study of Liver Diseases