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. Obesity and insulin resistance, cardinal features of the metabolic syndrome, are associated with enhanced lipolysis in adipose tissue (1, 2). This excessive lipolysis results in increased serum concentrations of free fatty acids (FFA), 2 augmenting their delivery to non-adipose tissues such as liver, heart, and pancreatic ␤-cells (2). Inundation of these tissues with FFA overwhelms fatty acid oxidative pathways with toxic cellular consequences. An advanced response to toxic FFA is cellular demise by apoptosis, termed lipoapoptosis (3). Hepatocyte lipotoxicity is particularly germane to injury in the liver, where it contributes to the syndrome of nonalcoholic fatty liver disease (NAFLD) (4). For example, the magnitude of hepatocyte lipoapoptosis correlates with hepatic disease severity (4). Thus, the mechanisms initiating lipoapoptosis are of biomedical interest and human health relevance. Lipotoxicity is likely multifactorial. Sustained endoplasmic reticulum (ER) stress (5-7), c-Jun N-terminal kinase (JNK) activation (8, 9), and oxidative stress (10) have all been implicated in lipotoxicity. Despite the fact that death receptors are potent mediators of cytotoxicity (11), especially in hepatic diseases, their contribution to lipotoxicity is incompletely defined. Fas, the prototype death receptor, has been implicated in adipocyte toxicity and inflammation (12), and its hepatic expression is increased in NAFLD (4). Tumor necrosis factor-␣ (TNF-␣) and TNF receptor-1 (TNFR-1) have also been implicated in hepatic steatosis (13)(14)(15). In contrast, the role of TNF-related apoptosis-inducing ligand (TRAIL) and its cognate death receptors (DR)-4 and -5 in lipotoxicity is understudied. Yet, increasing data implicate a critical role for DR5 in lipotoxicity. For example, DR5 expression is increased in steatotic hepatocytes and sensitizes hepatocytes to exogenous TRAIL cytotoxicity (16). Thus, the role of DR5 in lipoapoptosis merits further investigation.In this study, we explored the potential contribution of DR5 death signaling during lipoapoptosis by saturated FFA. The results implicate TRAIL death signaling by DR...

A Histone Deacetylase Inhibitor, OBP-801, and Celecoxib Synergistically Inhibit the Cell Growth with Apoptosis via a DR5-Dependent Pathway in Bladder Cancer Cells

“…S4B). Previously, Cazanave and colleagues and Eckhardt and colleagues reported that DR5 upregulation induced apoptosis in a TRAIL-independent manner (20,21). Therefore, we conclude that the combined treatment with OBP-801 and celecoxib mediates DR5 upregulation and induces apoptosis in a TRAIL-independent manner in bladder cancer cells.…”

ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R–mediated apoptosis

“…We confirmed that, at selected concentrations, those cytokines activated their respective signaling pathways: NF-κB, STAT1, and STAT3 (Supplemental Figure 7). DR5 expression in tumor cells can also be induced by ER stress via spliced XBP1, a major mediator of the IRE1 pathway, and C/EBP homologous protein (CHOP), a downstream molecule of the PERK pathway (24,(26)(27)(28)(29). The ER stress inducer tunicamycin caused significantly increased DR5 expression in BM PMNs and monocytes ( Figure 6, A and B).…”

RNASET2 is required for ROS propagation during oxidative stress-mediated cell death

“…[5][6][7][8][9] Compensatory incorporation of lipids into new membrane synthesis or triglyceride stores are likely to be initially protective, 10,11 but ultimately prove maladaptive because of the deleterious consequences of altered membrane composition on organelle function, 12 and because lipids may ultimately be mobilized from inert pools during prolonged exposure. 13 Similarly, whereas engagement of the endoplasmic reticulum (ER) stress machinery or generation of reactive oxygen species (ROS) can serve adaptive or productive signaling functions in response to lipid overload, extreme ER and oxidative stress engage cell death pathways.…”