Burn Plus Lipopolysaccharide Augments Endoplasmic Reticulum Stress and NLRP3 Inflammasome Activation and Reduces PGC-1α in Liver

Li, Diao; Marshall, Alexandra H.; Dai, Xiaojing; Bogdanovic, Elena; Abdullahi, Abdikarim; Amini-Nik, Saeid; Jeschke, Marc G.

doi:10.1097/shk.0000000000000075

Cited by 35 publications

(31 citation statements)

References 36 publications

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“…induces inflammasome activation in liver, augments hepatic endoplasmic reticulum (ER) stress and liver damage, thus contributing to metabolic derangement (7). Using this model, we observed increased fatty infiltration in liver tissue.…”

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confidence: 70%

Alternative Mechanism for White Adipose Tissue Lipolysis after Thermal Injury

Patsouris

Sadri

et al. 2015

Mol Med

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Extensively burned patients often suffer from sepsis, a complication that enhances postburn hypermetabolism and contributes to increased incidence of multiple organ failure, morbidity and mortality. Despite the clinical importance of burn sepsis, the molecular and cellular mechanisms of such infection-related metabolic derangements and organ dysfunction are still largely unknown. We recently found that upon endoplasmic reticulum (ER) stress, the white adipose tissue (WAT) interacts with the liver via inflammatory and metabolic signals leading to profound hepatic alterations, including hepatocyte apoptosis and hepatic fatty infiltration. We therefore hypothesized that burn plus infection causes an increase in lipolysis of WAT after major burn, partially through induction of ER stress, contributing to hyperlipidemia and profound hepatic lipid infiltration. We used a two-hit rat model of 60% total body surface area scald burn, followed by intraperitoneal (IP) injection of Pseudomonas Aeruginosa-derived lipopolysaccharide (LPS) 3 d postburn. One day later, animals were euthanized and liver and epididymal WAT (EWAT) samples were collected for gene expression, protein analysis and histological study of inflammasome activation, ER stress, apoptosis and lipid metabolism. Our results showed that burn plus LPS profoundly increased lipolysis in WAT associated with significantly increased hepatic lipid infiltration. Burn plus LPS augmented ER stress by upregulating CHOP and activating ATF6, inducing NLRP3 inflammasome activation and leading to increased apoptosis and lipolysis in WAT with a distinct enzymatic mechanism related to inhibition of AMPK signaling. In conclusion, burn sepsis causes profound alterations in WAT and liver that are associated with changes in organ function and structure.

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confidence: 70%

Alternative Mechanism for White Adipose Tissue Lipolysis after Thermal Injury

Patsouris

Sadri

et al. 2015

Mol Med

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“…A very recent study by Diao et al reported that burn plus LPS promotes the inflammasome and ER stress in rat liver as evidence with increased level of CHOP and sXBP1[99]. Although, these observations increase our knowledge of the biological mechanisms in the context of ER stress and sepsis and simultaneously shed light on new targets and suggest novel strategies for the treatment of this condition.…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic Reticulum Stress in Sepsis

Khan

Yang

Wang

2015

Shock

115

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Sepsis is an enormous public health issue and the leading cause of death in critically ill patients in intensive care units (ICU). Overwhelming inflammation, characterized by cytokine storm, oxidative threats, and neutrophil sequestration is an underlying component of sepsis-associated organ failure. Despite recent advances in sepsis research, there is still no effective treatment available beyond the standard of care and supportive therapy. To reduce sepsis-related mortality, a better understanding of the biological mechanism associated with the sepsis is essential. Endoplasmic reticulum (ER), a subcellular organelle is responsible for the facilitation of protein folding and assembly and involved in several other physiological activities. Under the stress and inflammation condition, ER loses the homeostasis in its function, which is termed as ER stress. During ER stress, unfolded protein response (UPR) is activated to restore ER function to its normal balance. However, once the stress is beyond the compensatory capacity of UPR or protracted, the apoptosis would be initiated by triggering cell injuries, even to cell death. As such, ER stress and UPR are reported to be implicated in several pathological and inflammatory conditions. Although the detrimental role of ER stress during infections has been demonstrated, there is growing evidences that ER stress participate in the pathogenesis of sepsis. In this review, we summarize the current research in the context of ER stress and UPR signaling associated with sepsis and its related clinical conditions, such as trauma- hemorrhage, and ischemia/reperfusion (I/R) injury. We also discuss the potential implication of ER stress as a novel therapeutic target and prognostic marker in patients with sepsis.

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“…The activation of hepatic NLRP3 inflammasome has also been reported in rats undergoing burn injury combined with LPS injection. 37 We have further demonstrated that SRT1720 treatment inhibits the expression of NLRP3 and ASC, two major protein components involved in forming a inflammasome complex, in the liver of septic mice. We have also observed a reduction of IL-1 β and IL-18 expression in septic mice treated with SRT1720.…”

Section: Discussionmentioning

confidence: 68%

SRT1720, a sirtuin 1 activator, attenuates organ injury and inflammation in sepsis

Khader

Yang

Hansen

et al. 2017

Journal of Surgical Research

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Background Sepsis affects 800,000 patients in the US annually with a mortality rate of up to 30%. Recent studies suggest that sepsis-associated metabolic derangements due to hypoxic tissue injury, impaired oxygen utilization, and mitochondrial dysfunction contribute to mortality. Sirtuin 1 (Sirt1) is a crucial modulator of energy metabolism during starvation states and has anti-inflammatory effects. Here, we hypothesized that SRT1720, a Sirt1 activator, could attenuate the severity of sepsis. Materials and Methods Male C57BL/6 mice (20–25g) were subjected to cecal ligation and puncture (CLP) to induce sepsis. SRT1720 (5 or 20 mg/kg BW) or 10% dimethyl sulfoxide (vehicle) in 0.2 ml saline was injected intravenously at 5 h after CLP. Control animals were not subjected to any surgery. Blood and liver samples were harvested at 20 h after CLP for analysis. Results Administration of SRT1720 markedly reduced the serum levels of tissue injury markers (AST, ALT, and LDH) and renal injury markers (BUN and creatinine) in a dose-dependent manner after CLP. Furthermore, the levels of proinflammatory cytokines IL-1β and IL-6 in the serum and liver were significantly inhibited by SRT1720 treatment after CLP. SRT1720 treatment resulted in a significantly decreased mRNA expression of inflammasome components [nucleotide oligomerization domain-like receptor protein 3 (NLRP3), adapter apoptosis-associated speck-like protein containing caspase-recruitment domain (ASC), IL-1β, and IL-18] in the liver, compared to the vehicle group. Conclusions SRT1720 treatment attenuates multi-organ injury in septic mice. SRT1720 treatment also decreases the production of proinflammatory cytokines and reduces inflammasome activation. Thus, pharmacologic stimulation of Sirt1 may present a promising therapeutic strategy for sepsis.

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Burn Plus Lipopolysaccharide Augments Endoplasmic Reticulum Stress and NLRP3 Inflammasome Activation and Reduces PGC-1α in Liver

Cited by 35 publications

References 36 publications

Alternative Mechanism for White Adipose Tissue Lipolysis after Thermal Injury

Alternative Mechanism for White Adipose Tissue Lipolysis after Thermal Injury

Endoplasmic Reticulum Stress in Sepsis

SRT1720, a sirtuin 1 activator, attenuates organ injury and inflammation in sepsis

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