Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis #

Witek, Rafal P.; Stone, WC; Karaca, Fatma; Syn, Wing–Kin; Pereira, Thiago A.; Agboola, Kolade M.; Omenetti, Alessia; Jung, Youngmi; Teaberry, Vanessa; Choi, Steve S.; Guy, Cynthia D.; Pollard, John R.; Charlton, Peter; Diehl, Anna Mae

doi:10.1002/hep.23167

Cited by 216 publications

(183 citation statements)

References 25 publications

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“…Thus, on the basis of our data, it appears that HD diet induces a local inflammatory response, resulting in activation of the TGF-β/Smad2 signaling, which may potentially contribute to development of insulin resistance and to late liver and kidney fibrosis (not yet detectable at the time point here measured). Our observation is in concordance with previous reports indicating that local inflammation precedes fibrosis, when the latter is determined by measuring collagen production and accumulation (34,35). Our data showing reduced activation of the TGF-β/Smad3 signaling in KO mice exposed to the same diet manipulation raise the possibility of an involvement of the NLRP3 inflammasome pathway in modulation of the early markers of fibrosis.…”

Section: Discussionsupporting

confidence: 93%

Targeting the NLRP3 inflammasome to Reduce Diet-induced Metabolic Abnormalities in Mice

Chiazza

Couturier-Maillard

Benetti

et al. 2015

Mol Med

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Although the molecular links underlying the causative relationship between chronic low-grade inflammation and insulin resistance are not completely understood, compelling evidence suggests a pivotal role of the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Here we tested the hypothesis that either a selective pharmacological inhibition or a genetic downregulation of the NLRP3 inflammasome results in reduction of the diet-induced metabolic alterations. Male C57/BL6 wild-type mice and NLRP3 -/-littermates were fed control diet or high-fat, high-fructose diet (HD). A subgroup of HD-fed wild-type mice was treated with the NLRP3 inflammasome inhibitor BAY 11-7082 (3 mg/kg intraperitoneally [IP]). HD feeding increased plasma and hepatic lipids and impaired glucose homeostasis and renal function. Renal and hepatic injury was associated with robust increases in profibrogenic markers, while only minimal fibrosis was recorded. None of these metabolic abnormalities were detected in HD-fed NLRP3 -/-mice, and they were dramatically reduced in HD-mice treated with the NLRP3 inflammasome inhibitor. BAY 11-7082 also attenuated the diet-induced increase in NLRP3 inflammasome expression, resulting in inhibition of caspase-1 activation and interleukin (IL)-1β and IL-18 production (in liver and kidney). Interestingly, BAY 11-7082, but not gene silencing, inhibited nuclear factor (NF)-κB nuclear translocation. Overall, these results demonstrate that the selective pharmacological modulation of the NLRP3 inflammasome attenuates the metabolic abnormalities and the related organ injury/dysfunction caused by chronic exposure to HD, with effects similar to those obtained by NLRP3 gene silencing.

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Section: Discussionsupporting

confidence: 93%

Targeting the NLRP3 inflammasome to Reduce Diet-induced Metabolic Abnormalities in Mice

Chiazza

Couturier-Maillard

Benetti

et al. 2015

Mol Med

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“…Apoptotic cell death generates apoptotic bodies, which are phagocytosed by tissue macrophages (Kupffer cells) and to a lesser degree also by HSCs through interaction with the phos- (29). However, although a pan-caspase inhibitor reduced serum transaminases in a short trial in patients with HCV without affecting viral replication, other early-phase human studies have been less successful.…”

Section: Reduction Of Inflammation/tissue Injury (Hepatoprotectants)mentioning

confidence: 99%

Therapeutic targets in liver fibrosis

Fallowfield

2011

American Journal of Physiology-Gastrointestinal and Liver Physi

116

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Detailed analysis of the cellular and molecular mechanisms that mediate liver fibrosis has provided a framework for therapeutic approaches to prevent, slow down, or even reverse fibrosis and cirrhosis. A pivotal event in the development of liver fibrosis is the activation of quiescent hepatic stellate cells (HSCs) to scar-forming myofibroblast-like cells. Consequently, HSCs and the factors that regulate HSC activation, proliferation, and function represent important antifibrotic targets. Drugs currently licensed in the US and Europe for other indications target HSC-related components of the fibrotic cascade. Their deployment in the near future looks likely. Ultimately, treatment strategies for liver fibrosis may vary on an individual basis according to etiology, risk of fibrosis progression, and the prevailing pathogenic milieu, meaning that a multiagent approach could be required. The field continues to develop rapidly and starts to identify exciting potential targets in proof-of-concept preclinical studies. Despite this, no antifibrotics are currently licensed for use in humans. With epidemiological predictions for the future prevalence of viral, obesity-related, and alcohol-related cirrhosis painting an increasingly gloomy picture, and a shortfall in donors for liver transplantation, the clinical urgency for new therapies is high. There is growing interest from stakeholders keen to exploit the market potential for antifibrotics. However, the design of future trials for agents in the developmental pipeline will depend on strategies that enable equal patient stratification, techniques to reliably monitor changes in fibrosis over time, and the definition of clinically meaningful end points. antifibrotic therapy; hepatic stellate cell MECHANISMS AND MEDIATORS OF LIVER FIBROGENESIS AND FIBROSIS REGRESSIONAs our understanding of the complex biological processes that regulate liver scarring increases, points of intervention in the fibrotic cascade are relentlessly uncovered. Key mechanisms and mediators are outlined below, to highlight emerging therapeutic targets (Fig. 1). Liver Fibrogenesis and the Role of the Hepatic Stellate Cell-MyofibroblastLiver fibrogenesis is orchestrated by a heterogeneous population of profibrogenic myofibroblasts (MFBs), the majority originating from hepatic stellate cells (HSCs), following a process termed "activation." Other sources of fibrogenic cells have recently been implicated, including portal fibroblasts and cells derived from the bone marrow (including fibrocytes) (7). A more controversial phenomenon is epithelial-to-mesenchymal transition, whereby epithelial cells (hepatocytes or cholangiocytes) undergo transdifferentiation to MFBs driven by bone morphogenic protein 7 and the hedgehog pathway, respectively, as well as a series of proinflammatory mediators. The relative contribution of these diverse precursors to fibrogenesis and the timing of their recruitment are unclear but may vary by disease etiology. In normal liver, quiescent HSCs store vitamin A in lipid droplets, but i...

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“…The toxin model of NASH utilizes coadministration of high-fat diet and a low-dose environmental toxin bromodichloromethane (BDCM) (7,31). The diet-induced model exposes mice to methyl-choline-deficient (MCD) diet for 8 wk (36,37). In a first ever report, we show that in both models of NASH there was an increased metabolic oxidative stress, which caused higher expression of P2X7 receptors.…”

mentioning

confidence: 90%

Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis

Das

Seth

Kumar

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Das S, Seth RK, Kumar A, Kadiiska MB, Michelotti G, Diehl AM, Chatterjee S. Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 305: G950 -G963, 2013. First published October 24, 2013 doi:10.1152/ajpgi.00235.2013.-Recent studies indicate that metabolic oxidative stress, autophagy, and inflammation are hallmarks of nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanisms that link these important events in NASH remain unclear. In this study, we investigated the mechanistic role of purinergic receptor X7 (P2X7) in modulating autophagy and resultant inflammation in NASH in response to metabolic oxidative stress. The study uses two rodent models of NASH. In one of them, a CYP2E1 substrate bromodichloromethane is used to induce metabolic oxidative stress and NASH. Methyl choline-deficient diet feeding is used for the other NASH model. CYP2E1 and P2X7 receptor gene-deleted mice are used to establish their roles in regulating metabolic oxidative stress and autophagy. Autophagy gene expression, protein levels, confocal microscopy based-immunolocalization of lysosome-associated membrane protein (LAMP)2A and histopathological analysis were performed. CYP2E1-dependent metabolic oxidative stress induced increases in P2X7 receptor expression and chaperone-mediated autophagy markers LAMP2A and heat shock cognate 70 but caused depletion of light chain 3 isoform B (LC3B) protein levels. P2X7 receptor gene deletion significantly decreased LAMP2A and inflammatory indicators while significantly increasing LC3B protein levels compared with wild-type mice treated with bromodichloromethane. P2X7 receptor-deleted mice were also protected from NASH pathology as evidenced by decreased inflammation and fibrosis. Our studies establish that P2X7 receptor is a key regulator of autophagy induced by metabolic oxidative stress in NASH, thereby modulating hepatic inflammation. Furthermore, our findings presented here form a basis for P2X7 receptor as a potential therapeutic target in the treatment for NASH.5,5-dimethyl-1-pyrroline N-oxide-nitrone adducts; lipid peroxidation; tyrosine nitration; cytokines; CYP2E1; light chain 3 isoform B; GABA-A receptor-associated protein NONALCOHOLIC STEATOHEPATITIS (NASH) is associated with metabolic oxidative stress, often ascribed to enhanced oxidation of membrane lipids, mitochondrial uncoupling of the electron transport chain, and higher cytochrome P450 enzyme activity (18,29,30). Metabolic oxidative stress leads to cellular stress and induces cell death mechanisms, which modulate inflammatory microenvironment in NASH (5, 24).Cell death mechanisms in disease pathogenesis are synonymous with necrosis, autophagy, and apoptosis; however, much attention is recently focused on the various roles of autophagy in cellular processes, inflammation, energy homeostasis, and immunity (8, 35). Despite increased attention on autophagy, the mechanisms tha...

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Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis #

Cited by 216 publications

References 25 publications

Targeting the NLRP3 inflammasome to Reduce Diet-induced Metabolic Abnormalities in Mice

Targeting the NLRP3 inflammasome to Reduce Diet-induced Metabolic Abnormalities in Mice

Therapeutic targets in liver fibrosis

Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis

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