Reactive Oxygen Species-Induced TXNIP Drives Fructose-Mediated Hepatic Inflammation and Lipid Accumulation Through NLRP3 Inflammasome Activation

Abstract

Aims: Increased fructose consumption predisposes the liver to nonalcoholic fatty liver disease (NAFLD), but the mechanisms are elusive. Thioredoxin-interacting protein (TXNIP) links oxidative stress to NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and this signaling axis may be involved in fructose-induced NAFLD. Here, we explore the role of reactive oxygen species (ROS)-induced TXNIP overexpression in fructose-mediated hepatic NLRP3 inflammasome activation, inflammation, and lipid accumulation. Results: Rats were fed a 10% fructose diet for 8 weeks and treated with allopurinol and quercetin during the last 4 weeks. Five millimolars of fructose-exposed hepatocytes (primary rat hepatocytes, rat hepatic parenchymal cells [RHPCs], HLO2, HepG2) were co-incubated with antioxidants or caspase-1 inhibitor or subjected to TXNIP or NLRP3 siRNA interference. Fructose induced NLRP3 inflammasome activation and proinflammatory cytokine secretion, janus-activated kinase 2/signal transducers and activators of transcription 3-mediated inflammatory signaling, and expression alteration of lipid metabolism-related genes in cultured hepatocytes and rat livers. NLRP3 silencing and caspase-1 suppression blocked these effects in primary rat hepatocytes and RHPCs, confirming that inflammasome activation alters hepatocyte lipid metabolism. Hepatocellular ROS and TXNIP were increased in animal and cell models. TXNIP silencing blocked NLRP3 inflammasome activation, inflammation, and lipid metabolism perturbations but not ROS induction in fructoseexposed hepatocytes, whereas antioxidants addition abrogated TXNIP induction and diminished the detrimental effects in fructose-exposed hepatocytes and rat livers. Innovation and Conclusions: This study provides a novel mechanism for fructose-induced NAFLD pathogenesis by which the ROS-TXNIP pathway mediates hepatocellular NLRP3 inflammasome activation, inflammation and lipid accumulation. Antioxidant-based interventions can inhibit the ROS-TXNIP pathway. Antioxid. Redox Signal. 22, 848-870.

Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation

“…Furthermore, it has been found that oxidative stress-mediated NLRP3 inflammasome activation also promoted lipid accumulation by deregulation of lipid metabolism-related genes expression in a high-fat diet model of NAFLD [87]. Consequently, a similar mechanism involving inflammasome initiation response blockage by quercetin may also underlie its modulatory effect on hepatic gene expression related to lipid metabolism alteration, reinforcing the role of this flavonol as a potential therapeutic strategy for preventing NAFLD development and progression.…”

Hepatitis B virus X protein promotes hepatocellular carcinoma invasion and metastasis via upregulating thioredoxin interacting protein

“…TXNIP was reported to be induced by stress stimulation, including infection, H 2 O 2 , ultraviolet and ROS (39,47). It is therefore a reasonable hypothesis that HBx may impact TXNIP expression in HBV-associated HCC tissues and HCC cells.…”

“…The ISHAK score of patients with HBV-associated HCC was based on the ISHAK scoring system (38). (21), and TXNIP expression may be induced by ROS stimulation (39). However, to the best of our knowledge, no previous studies have investigated the association between HBx and TXNIP expression in HBV-associated HCC tissues or HCC cells.…”

Potential Roles of Mitochondria-Associated ER Membranes (MAMs) in Traumatic Brain Injury

“…Thioredoxin-interacting protein (TXNIP) is another bridge between oxidative stress and NLRP3. During mitochondrial oxidative stress, TXNIP can mediate the activation of NLPR3 in primary rat hepatocytes and in THP1 macrophage cells (Zhang et al 2015;Zhou et al 2011). During ER stress, TXNIP could be induced by PERK and inositol-requiring enzyme 1 (IRE1) pathways and then induce IL-1b production by the NLRP3 inflammasome (Oslowski et al 2012).…”

“…During ER stress, TXNIP could be induced by PERK and inositol-requiring enzyme 1 (IRE1) pathways and then induce IL-1b production by the NLRP3 inflammasome (Oslowski et al 2012). When TXNIP was silenced, the activation of the NLRP3 inflammasome was blocked, which indicated that TXNIP expression is essential for NLRP3 inflammasome activation (Zhang et al 2015).…”