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Death receptor 5 signaling promotes hepatocyte lipoapoptosis.

ABSTRACT: Nonalcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA), endoplasmic reticulum (ER) stress, and hepatocyte lipoapoptosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5 (DR5) is significantly elevated in patients with nonalcoholic steatohepatitis, and steatotic hepatocytes demonstrate increased sensitivity to TRAIL-mediated cell death. Nonetheless, a role for TRAIL and/or DR5 in mediating lipoapoptotic pathways is unexplored. Here, we examined the contribution of DR5 death signaling to lipoapoptosis by free fatty acids. The toxic saturated free fatty acid palmitate induces an increase in DR5 mRNA and protein expression in Huh-7 human hepatoma cells leading to DR5 localization into lipid rafts, cell surface receptor clustering with subsequent recruitment of the initiator caspase-8, and ultimately cellular demise. Lipoapoptosis by palmitate was not inhibited by a soluble human recombinant DR5-Fc chimera protein suggesting that DR5 cytotoxic signaling is ligand-independent. Hepatocytes from murine TRAIL receptor knock-out mice (DR(-/-)) displayed reduced palmitate-mediated lipotoxicity. Likewise, knockdown of DR5 or caspase-8 expression by shRNA technology attenuated palmitate-induced Bax activation and apoptosis in Huh-7 cells, without altering induction of ER stress markers. Similar observations were verified in other cell models. Finally, knockdown of CHOP, an ER stress-mediated transcription factor, reduced DR5 up-regulation and DR5-mediated caspase-8 activation upon palmitate treatment. Collectively, these results suggest that ER stress-induced CHOP activation by palmitate transcriptionally up-regulates DR5, likely resulting in ligand-independent cytotoxic signaling by this death receptor.

SUBMITTER: Cazanave SC

PROVIDER: S-EPMC3234758 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Death receptor 5 signaling promotes hepatocyte lipoapoptosis.

Cazanave Sophie C SC Mott Justin L JL Bronk Steven F SF Werneburg Nathan W NW Fingas Christian D CD Meng X Wei XW Finnberg Niklas N El-Deiry Wafik S WS Kaufmann Scott H SH Gores Gregory J GJ

The Journal of biological chemistry 20110922 45

Nonalcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA), endoplasmic reticulum (ER) stress, and hepatocyte lipoapoptosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5 (DR5) is significantly elevated in patients with nonalcoholic steatohepatitis, and steatotic hepatocytes demonstrate increased sensitivity to TRAIL-mediated cell death. Nonetheless, a role for TRAIL and/or DR5 in mediating lipoapop ...[more]

PMID: 21941003

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Project description:BackgroundAlcohol consumption has been shown to disrupt hepatic lipid homeostasis. Long-chain acyl-CoA synthetase 1 (ACSL1) critically regulates hepatic fatty acid metabolism and lipid homeostasis by channeling fatty acids to lipid metabolic pathways. However, it remains unclear how ACSL1 contributes to the development of alcohol-associated liver disease (ALD).MethodsWe performed chronic alcohol feeding animal studies with hepatocyte-specific ACSL1 knockout (ACSL1Δhep) mice, hepatocyte-specific STAT5 knockout (STAT5Δhep) mice, and ACSL1Δhep based-STAT5B overexpression (Stat5b-OE) mice. Cell studies were conducted to define the causal role of ACSL1 deficiency in the pathogenesis of alcohol-induced liver injury. The clinical relevance of the STAT5-ACSL1 pathway was examined using liver tissues from patients with alcoholic hepatitis (AH) and normal subjects (Normal).ResultsWe found that chronic alcohol consumption reduced hepatic ACSL1 expression in AH patients and ALD mice. Hepatocyte-specific ACSL1 deletion exacerbated alcohol-induced liver injury by increasing free fatty acids (FFA) accumulation and cell death. Cell studies revealed that FFA elicited the translocation of BAX and p-MLKL to the lysosomal membrane, resulting in lysosomal membrane permeabilization (LMP) and thereby initiating lysosomal-mediated cell death pathway. Furthermore, we identified that the signal transducer and activator of transcription 5 (STAT5) is a novel transcriptional regulator of ACSL1. Deletion of STAT5 exacerbated alcohol-induced liver injury in association with downregulation of ACSL1, and reactivation of ACSL1 by STAT5 overexpression effectively ameliorated alcohol-induced liver injury. In addition, ACSL1 expression was positively correlated with STAT5 and negatively correlated with cell death was also validated in the liver of AH patients.ConclusionsACSL1 deficiency due to STAT5 inactivation critically mediates alcohol-induced lipotoxicity and cell death in the development of ALD. These findings provide insights into alcohol-induced liver injury.

Project description:Acute liver failure (ALF) is a rare entity but exhibits a high mortality. The mechanisms underlying ALF are not completely understood. The present study explored the role of the hepatic B cell leukemia-3 (Bcl-3), a transcriptional regulator of nuclear factor-kappa B (NF-κB), in two independent models of ALF. We employed a recently developed transgenic mouse model in a C57BL6/J background comparing wild-type (WT) and transgenic littermates with hepatocyte-specific overexpression of Bcl-3 (Bcl-3Hep) in the ALF model of d-galactosamine (d-GalN) and lipopolysaccharide (LPS). Additionally, the apoptosis-inducing CD95 (FAS/APO-1)-ligand was explored. Bcl-3Hep mice exhibited a significant protection from ALF with decreased serum transaminases, decreased activation of the apoptotic caspases 8, 9, and 3, lower rates of oxidative stress, B-cell lymphoma 2 like 1 (BCL2L1/BCL-XL) degradation and accompanying mitochondrial cytochrome c release, and ultimately a decreased mortality rate from d-GalN/LPS compared to WT mice. d-GalN/LPS treatment resulted in a marked inflammatory cytokine release and stimulated the activation of signal transducer and activator of transcription (STAT) 3, c-Jun N-terminal kinases (JNK) and extracellular signal-regulated kinase (ERK) signaling comparably in the hepatic compartment of Bcl-3Hep and WT mice. However, in contrast to the WT, Bcl-3Hep mice showed a diminished rate of IkappaB kinase-beta (IKK-β) degradation, persistent receptor interacting protein kinase (RIPK) 1 function and thus prolonged cytoprotective nuclear factor-kappa B (NF-κB) p65 signaling through increased p65 stability and enhanced transcription. Likewise, Bcl-3 overexpression in hepatocytes protected from ALF with massive hepatocyte apoptosis induced by the anti-FAS antibody Jo2. The protection was also linked to IKK-β stabilization. Overall, our study showed that Bcl-3 rendered hepatocytes more resistant to hepatotoxicity induced by d-GalN/LPS and FAS-ligand. Therefore, Bcl-3 appears to be a critical regulator of the dynamics in ALF through IKK-β.

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Death receptor 5 signaling promotes hepatocyte lipoapoptosis.

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Death receptor 5 signaling promotes hepatocyte lipoapoptosis.

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