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

Abstract

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 death—so far characterized as hepatocyte apoptosis—represents 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.Subject Categories Digestive System; Metabolism

Nonalcoholic Fatty Liver Disease

“…Yet another pathway via which fatty acids can kill hepatocytes is through activation of death receptors. Several death receptors (FAS, DR5(also known as TRAIL-R2), TNFR1) are up-regulated on hepatocytes in the setting of steatosis; death receptor activation has been implicated as an important stimulus to hepatocyte apoptosis and necroptosis in NASH [55][56][57][58] . Whether hedgehog stimulates fibrosis through direct effects on stellate cells or indirect effects on fatty liver injury is currently under study 75 .…”

Inhibition of Necroptosis Attenuates Kidney Inflammation and Interstitial Fibrosis Induced By Unilateral Ureteral Obstruction

“…Importantly, numerous studies focused on necroptosis in recent years, partly because its inhibition, either genetically or with small-molecule inhibitors, is reported to reduce the disease severity in skin and multi-organ inflammation in sharpin mutant mice, systemic inflammation induced by TNF, atherosclerosis in Ldlr or Apoe mutant mice [14], dsRNA-induced retinal degeneration [15], rd10 model of retinitis pigmentosa [16], myocardial infarction [17], steatohepatitis [18,] and ethanol-induced liver injury [19]. Thus, while necroptosis appears to mediate host defense against virus-induced inflammation [20], its inhibition in certain contexts may have therapeutic potential.…”

Down-regulation of miR-192-5p protects from oxidative stress-induced acute liver injury

“…Moreover, stimulation of hepatoma cells with TNF and IL-1β led to miR-192-5p downregulation in vitro ( Figure 1F and Supplementary Figure S2). To examine whether miR-192-5p represents a direct target of NF-κB, we transfected Hepa1-6 cells with a dominant active variant of IKKβ ( [30], Figure 1G, left panel). In line with the hypothesis that miR-192 expression is dependent on NF-κB, miR-192 expression was lower ( Figure 1G, right panel) when NF-κB was constitutively active.…”