Open Access
Review

Inflammasomes in non-alcoholic fatty liver disease

Jia Xiao1,2,3,George L. Tipoe3,*
1
Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, 510632, China
2
National Key Disciplines for Infectious Diseases, Shenzhen Third People’s Hospital, Shenzhen, 518112, China
3
School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
DOI: 10.2741/4414 Volume 21 Issue 4, pp.683-695
Published: 01 January 2016
(This article belongs to the Special Issue Research update on liver Immunology)
*Corresponding Author(s):  
George L. Tipoe
E-mail:  
tgeorge@hku.hk
Abstract

Non-alcoholic fatty liver disease (NAFLD) is a leading liver disorder in the world. Inflammation is one of the most important pathological events during the development of NAFLD and also represents the hallmark between simple steatosis and non-alcoholic steatohepatitis (NASH). Inflammasomes are novel protein complex platforms assembled in response to pattern-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Currently, there are several identified inflammasomes, including nod-like receptor protein (NLRP)-1, 2, 3, 6, 10, 12, NLRC4 and absent in melanoma 2 (AIM2) inflammasomes. In the liver, inflammasomes are primarily expressed in immune cells. However, increasing evidence suggests that their expressions in other types of cells in the liver are also present. In general, inflammasomes are up-regulated in various liver diseases. In NAFLD, it is reported that the levels of inflammasome components (e.g. NLRPs, caspase-1, IL-1β and IL-18) are elevated. Silence of these components attenuates hepatic injury. Collectively, the main purposes of this review are to examine the recent progress of hepatic inflammasome research and to discuss possible directions of therapeutic strategy and development against NAFLD.

Key words

Non-alcoholic Fatty Liver; Inflammasome, Metabolic Disorders, Review

2. Introduction

The term non-alcoholic fatty liver disease (NAFLD) actually include a spectrum of abnormal liver conditions which are not attributed to the abuse of alcohol, from the development of simple steatosis (fat accumulation in the liver without inflammation) to non-alcoholic steatohepatitis (NASH; with hepatic steatosis, inflammation and fibrosis). In contrast, chronic excessive use of alcohol (over 12 ounces of 4 - 5% beer, or 6 ounces of 8 - 10% wine, or 2 ounces of 45% hard liquor/whiskey everyday) can lead to alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), alcoholic cirrhosis and cancer (1). It should be noted that, although necessary, excessive alcohol use is not sufficient to cause AFLD, since only 1 in 5 heavy drinkers develops alcoholic hepatitis, and 1 in 4 develops cirrhosis (2). The prevalence of NAFLD in adults is 10-30% and its prevalence is increasing in Western countries as well as in China because of the epidemic rise in obesity and diabetes (3-5). It is estimated that 20% of NASH cases will slowly progress to cirrhosis and even liver cancer (6).

Pathogenic mechanisms related to the initiation and progressions of NAFLD remain not fully characterized. Despite the fact that the causative factors for AFLD and NAFLD are somehow different, both diseases share the same natural history (i.e. from simple steatosis to hepatitis to cirrhosis). In addition, the clinical symptoms of AFLD and NAFLD are quite similar (7). The liver and the gastrointestinal tract are the main sites conducting alcohol metabolism. After alcohol consumption, alcohol dehydrogenase and acetaldehyde dehydrogenase induce the reduction of nicotinamide adenine dinucleotide (NAD) to NADH (reduced form of NAD), which then cause fatty liver through the inhibition of gluconeogenesis and fatty acid oxidation. Cytochrome P450 2E1, another metabolic pathway of alcohol, will be induced to produce free radicals to damage the liver, leading to the occurrence of inflammation, chemoattraction, necrosis and apoptosis (8). For NAFLD, to date, the most recognized disease model is the “multiple-parallel hit model” in which the dysregulated lipid metabolism and insulin resistance are considered as the first hit to the liver. Then the following hits include fibrosis, necrosis, apoptosis, oxidative stress and inflammation which will lead to the progression from steatosis to NASH (9). Among these pathological events, the role of inflammation in the pathogenesis of NAFLD received massive attention during the past years because it is the central event that links the upstream insulin resistance/steatosis and downstream cell injury, which is related to the progression of cirrhosis (10).

In clinical practice, NAFLD can be retarded or reversed to normal hepatic conditions when appropriate treatments are implemented. To date, there are two major categories of NAFLD therapies: (1) lifestyle interventions (such as weight reduction, dietary modification, and physical exercise) and (2) pharmaceutical therapies. Weight reduction and dietary modification are the most recognized strategies for the prevention and control of NAFLD (11).

3. Inflammation in NAFLD

The main difference between simple steatosis and NASH is the development of chronic inflammation. Recent reviews consider simple steatosis to be a benign and non-progressive condition, while NASH may reflect different disease entities (12). Patients with steatohepatitis may show none or low level of steatosis, suggesting that inflammation could occur first (13). In addition, treatment with anti-tumor necrosis factor (TNF) antibody and anti-diabetic drug metformin improved hepatic steatosis in ob/ob mice (14). Applications of antioxidants are also shown to attenuate hepatic inflammation in alcohol-induced liver diseases (15). Very interestingly, loss of Kupffer cells, the local macrophage of the liver, leads to steatotic development probably due to decreased level of interleulin-10 (IL-10) (16).

Inflammation during the pathogenesis of NASH is also positively related with disrupted lipid metabolism, oxidative stress, and apoptosis. It is well known that increased lipid accumulation leads to lipid peroxidation and inflammation. For example, in the liver, oxidized low-density lipoprotein (LDL) can bind to scavenger receptors on the surface of Kupffer cells (e.g. CD36) to promote inflammatory responses (17). Other studies also found that TNF-α was capable of inhibiting hepatic cholesterol elimination and activating its synthesis, contributing to the decrease of high-density lipoprotein (HDL)-cholesterol and the increase of LDL-cholesterol (18, 19). Oxidative stress is also a direct inducer and downstream target of hepatic inflammation during the progression of NASH. Increased oxidative stress in NASH patients results in pro-oxidative and pro-inflammatory environments. For example, hepatic oxidative stress activates transcriptional factor nuclear factor-kappa B (NF-κB), which in turn increases the secretion of pro-inflammatory cytokines and chemokines, resulting in elevated apoptosis, neutrophil chemotaxis, and hepatic stellate cell activation (20). Our studies also demonstrated that, when appropriate antioxidant/hepato-protective agents were applied, the increased expression of inducible nitric oxide synthase (iNOS), which is the key link between oxidative stress and inflammation, in NASH rodents were significantly inhibited (21, 22).

The Toll-like receptor (TLR)-mediated pathways, including c-Jun NH2-terminal kinase (JNK), is another key event in the progression of NASH. TLR4 is the receptor in response to lipopolysaccharide (LPS) and other kinds of endotoxins. The interaction between TLR4 and its adaptor protein myeloid differentiation factor 88 (MyD88) triggers a downstream signaling cascade, leading to activation of the NF-κB pathway (23). In a murine model, genetic deletion of TLR4 shows significantly attenuated hepatic injury induced by NASH through the actions of Kupffer cells (24). Moreover, in leptin deficient ob/ob mice, it is suggested that probiotic treatment prevented histological changes and insulin resistance associated with NASH (14). Since high-fat diet feeding induces the decrease of bifidobacteria, which can reduce intestinal endotoxin levels and improve mucosal barrier functions (25), a link between modulation of gut bacteria, endotoxemia, and inflammation in NASH should be considered in the therapy of NAFLD.

4. Inflammasomes

4.1. Discovery

In 2002, Martinon et al. reported a caspase-activating complex that they called the inflammasome (comprises caspase-1, caspase-5, Pycard/Asc, and NALP1, a Pyrin domain-containing protein sharing structural homology with NODs) in a cell-free system (26). They found that immune-depletion of Pycard can abrogate pro-inflammatory caspase activation and pro-IL-1β processing after the challenge of LPS. This is the first time that the term inflammasome was introduced. However, the first member of the inflammasome family – Nod-like receptor protein (NLRP3) was discovered in 2001. Hoffman et al. identified a gene with four distinct mutations that segregated with the disorder familial cold auto-inflammatory syndrome (FCAS) and Muckle−Wells syndrome (MWS). This gene, called CIAS1 (referred to NLRP3 later), encodes a protein with a pyrin domain, a nucleotide-binding site (NBS, NACHT subfamily) domain and a leucine-rich repeat (LRR) motif region (27). After that, other members of the inflammasome family have been identified one after another.

4.2. Classification

To date, a number of inflammasomes have been discovered and characterized, including NLRP1, 2, 3, 6, 10, 12, NLRC4 and AIM2. Although differing in ligand recognition, downstream pathway, and biological functions, the activation of caspase-1 is the core function of almost all of the inflammasomes.

The NLRP1 inflammasome is the first functionally described member of the inflammasome family. It consists of NACHT, PYD (pyrin domain) and LRR domains. NLRP1 can be activated by anthrax toxin or chemotherapy (28, 29). Importantly, in the presence of ASC, its activity can be further enhanced (30). Unlike other inflammasomes, NLRP1 inflammasome is able to be located in the nucleus (31).

The NLRP2 inflammasome was discovered in 2012. Minkiewicz et al. reported that human astrocytes express an inflammasome consisting of NLRP2, ASC, and caspase-1. Upon the activation by ATP, NLRP2 is activated to promote the processing of inflammatory caspase-1 and IL-1β (32). However, the expression pattern of NLRP2 inflammasome in other organs as well as its specific functions in various diseases needs further investigations.

Unlike other inflammasomes and many innate receptors, the NLRP3 inflammasome is a proteolytic caspase-1-activating platform in which caspase-1 does not involve in apoptosis too much. Instead, it is capable of cleaving the pro-forms of IL-1β and IL-18 in the cytoplasm, to release these two potent pro-inflammatory cytokines from the cell. Activated caspase-1 also has the ability to induce the secretion of IL-1α and high mobility group box 1 (HMGB1), as well as to initiate a lytic form of cell death named pyroptosis (33). The NLRP3 inflammasome responds to a spectrum of stimuli, including various types of molecules, bacteria, and viruses (34). Therefore, it becomes a novel therapeutic target for related diseases, including metabolic disorders and pathogen infections (35).

The NLRP6 inflammasome plays vital roles in maintaining intestinal homeostasis and balance of intestinal microbiota through regulation of IL-18 (36). Mice with NLRP6 deficiency are more susceptible to intestinal inflammation and chemically induced colitis, suggesting its functions in mucosal self-renewal and proliferation (37). A new report found that the NLRP6 inflammasome regulates goblet cell mucus secretion through induction of autophagy. Alteration of its expression damages mucus layer, leading to susceptibility to infection (38).

NLRP10 is the only NLR lacking the putative ligand-binding leucine-rich-repeat domain. Thus, it is considered as the negative regulator of other inflammasomes (39). Moreover, NLRP10 cannot function through an inflammasome to regulate caspase-1. Instead, deficiency of NLRP10 in mice shows a profound defect in helper T-cell-driven immune responses to a spectrum of stimuli (e.g. LPS) (40).

NLRP12 is found to be associated with ASC and then to form an active IL-1β-maturing inflammasome (40). It is also involved in the pathogenesis of periodic fever syndromes (PFS) (41) and the host defense against Yersinia pestis (42). A new study identified that NLRP12/NLRP3-dependent activation of caspase-1 might be a central event in mediating the hypersensitivity to secondary bacterial infection in malaria (43). Alongside the roles of NLRP1 and NLRP3, NLRP12 participates in the protection from acute colitis through negative regulation of non-canonical NF-κB signaling. That is, Nlrp12-/- mice exhibit more severe colitis upon dextran sodium sulphate (DSS) administration than its wild-type littermates (44).

One of the major functions of the NLRC4 inflammasome is to activate caspase-1 to fight against the infection of Gram-negative bacteria, such as Salmonella, Legionella, and Shigella. For example, the NLRC4 inflammasome is activated upon the cytosolic delivery of flagellin or the bacterial rod protein PrgJ through the type III secretion system (T3SS) in the infected macrophage by Salmonella (45). Very recently, the phosphorylation of NLRC4 at Ser533 is found to be vital for its activation with the help of kinase Pkcδ (46) or not (47).

AIM2 is a cytosolic inflammasome sensing double-strand DNA (dsDNA). It can be activated by virus, bacterial, and mammalian host DNA to trigger the release of caspase-1 (48, 49). In autoimmune diseases, the AIM2 inflammasome recognizes the mammalian DNA which acts as a contributory factor to the disease pathogenesis (50). In the central nervous system (CNS), the AIM2 inflammasome is triggered by dsDNA in cells harboring intracellular bacterial and then to secret pro-inflammatory cytokines (51).

4.3. Signaling pathway of the NLRP3 inflammasome

Although a variety of molecular structures such as pattern-associated molecular pattern (PAMP)- and damage-associated molecular pattern (DAMP)-containing molecules are capable of activating NLRP3 inflammasome, at current stage, it is considered that NLRP3 is not likely to recognize these motifs except for cellular homeostasis (e.g. cell stress). One of these examples is endoplasmic reticulum (ER) stress. Several ER stressors can induce the assembly of the NLRP3 inflammasome and the secretion of IL-1β and IL-18, probably independent of known unfolded protein response (UPR) initiators (PERK, IRE1α, and ATF6) (52). Our study and other recent studies also identified the key role of thioredoxin-interacting protein (TXNIP) in ER stress-induced activation of the NLRP3 inflammasome (53-55), although another recent study using TXNIP-knockout macrophages found that TXNIP cannot directly activate NLRP3 (56).

Intracellular Ca2+ can also promote the NLRP3 inflammasome activation. For instance, one study suggests that this process is through the release of mitochondrial reactive oxygen species (mROS) and mitochondrial DNA (mtDNA) (57). G protein-coupled Ca2+-sensing receptors, CASR and GPRC6A, are able to trigger the NLRP3 activation, via a PLC-IP3-IP3R cascade (58). Moreover, recent studies found that Ca2+-permeable channels, such as transient potential melastatin-like 2 (TRPM2), TRPV2 and TRPM7, are required for the activation of NLRP3 on the basis of Ca2+ influx (59, 60).

Intrinsic and extrinsic apoptotic pathways are inducers of the NLRP3 inflammasome. Recent studies revealed that the inhibitors of apoptosis (IAPs) regulate inflammasomes in both positive and negative manners. Deletion of the gene encoding cIAP2 impairs the activation of NLRP3 (61). Very interestingly, deletion of all three IAPs (XIAP, cIAP1, and cIAP2) leads to NLRP3-caspase-1-dependent and caspase-8-dependent IL-1β activation (62). As a key component of the extrinsic apoptotic pathway, caspase-8 can trigger the cleavage of both IL-1β and IL-18 by engaging cell surface receptors, such as FAS (63), TLRs (64), and C-type lectin receptor dectin-1 (65). It activates IL-1β through two distinct pathways: active caspase-8 directly process IL-1β in response to signals outside the cells, while deficiency or insufficient activation of caspase-8 leads to NLRP3 activation through RIP3 signaling (66).

In recent literatures, two important regulators of inflammasomes were identified and characterized namely guanylate-binding protein 5 (GBP5) and double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) (67, 68). GBP5 is a member of the GBP family which promotes the activation of the NLRP3 inflammasome by ATP, nigericin, and bacteria. It binds to the PYRIN domain of NLRP3 and forms a tetrameric structure to modulate the NLRP3-ASC oligomerization. Upon induction of agonist, PKR is autophosphorylated. When PKR is inactivated by genetic deletion or pharmacological inhibition, the responses of inflammasome to double-stranded RNA, ATP, monosodium urate, adjuvant aluminium, rotenone, live Escherichia coli, anthrax lethal toxin, DNA transfection and Salmonella typhimurium infection are significantly impaired. However, He et al., reported that cells isolated from Pkr-deletion mouse strains, PKR shows no obvious effect on NLRP3 activation (69). Reason for contradictory observations regarding PKR on NLRP3 remains unclear.

4.4. Inflammasomes in the liver

Hepatocytes are the most abundant epithelial cells in the liver. In an adult human, there are approximately 1011 hepatocytes in total, which represent around 60% of all cells and around 80% mass of the liver. The liver is also comprised of immune cells, such as Kupffer cells, neutrophil leukocytes, dendritic cells, T/B cells, and NK/NKT cells. Innate immune cells are the major source of inflammasome production in the liver. There is increasing evidence that inflammasomes are functionally active in non-immune cells, including hepatocytes (70), stellate cells (71), endothelial cells (72), and myofibroblasts (73). Kupffer cells express most kinds of inflammasomes except NLRP1 (31).

HBV core antigen is able to induce the secretion of IL-18 from human peripheral blood mononuclear cells (PBMCs) and from HBeAg negative patients, suggesting the possible role of inflammasome activation in chronic HBV infection (74, 75). Du et al. showed that in HBV associated glomerulonephritis (HBV-GN) patients, the expression of AIM2 in renal biopsy specimen is significantly increased to regulate the expression of caspase-1, IL-1β, and IL-18 (76).

In chronic HCV infection patients, the serum and hepatic levels of IL-1β are increased. When anti-HCV therapy is applied, serum expression of IL-1β and caspase-1 is reduced (77). In HCV-infected human hepatoma cells, the HCV is sensed by NLRP3 protein to recruit ASC for the assembly of inflammasome and the secretion of IL-1β (78). Negash et al. also confirmed that the increased level of NLRP3 inflammasome and IL-1β from Kupffer cells might be a component of HCV immunopathology in HCV-infected patients (79).

Acetaminophen (APAP)-induced hepatotoxicity is still the leading cause of drug-induced liver injury in the U.S. (80). In this case, DAMPs are released from damaged hepatic cells to initiate inflammatory responses through TLRs and NLRs/inflammasomes (e.g. ATP and MSU) (81). Controversial results have been reported on the role of inflammasomes in APAP-induced hepatotoxicity. A majority of studies found that IL-1β is up-regulated at both transcriptional and translational levels in APAP-induced toxicity in animal models (82-84). But a small clinical study in children and adolescents pointed out that APAP overdose did not induce the elevation of serum IL-1β level (85). Blocking antibodies against IL-1α, IL-1β, and IL-1R lead to amelioration of APAP-induced liver injury (83). Deficiency of IL-18 also reproduces similar results (72). However, another study found that IL-1R knockout mice, or mice lacking of inflammasome components (NLRP3, ASC, and caspase-1) showed no protection against APAP-induced liver injury (86). These contradictory results may be attributed to the diversity of IL-1 and IL-18 roles in the pathogenesis of liver diseases and the observation timing, animal age, and gender discrepancy in the experimental design (87).

In the clinics, the main features of ischemia-reperfusion (I/R) injury include cellular necrosis, release of DAMPs, inflammation, oxidative stress, and disruption of liver sinusoidal endothelial cells (88). In the presence of antioxidant N-acetylcysteine, caspase-1 is inhibited and the liver I/R injury is attenuated (89). Consistent with this result, silence of NLRP3 ameliorates hepatic I/R injury via inhibition of caspase-1 and NF-κB activity (90). Application of IL-1R antagonist or IL-18 neutralizing antibody also significantly ameliorates hepatic I/R injury in animal models, probably through TLR4 and TLR9 (91-93).

In both clinical patients and animals with alcoholic fatty liver disease (AFLD), the serum level of IL-1β is significantly increased when compared with normal subjects (94). It is also found that IL-1β signaling is required for the development of alcohol-induced liver steatosis and IL-1R antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis (95). Our recent study also found that the NLRP3 inflammasome components (NLRP3, ASC, IL-1β, and caspase-1) are up-regulated in a cell-based alcoholic liver injury model (55).

4.5. Inflammasomes in NAFLD

Up-regulation of both IL-1β mRNA and protein is observed in diet-induced NASH mice models, methionine-choline-deficient (MCD) diet, high-fat diet (HFD) and choline-deficient amino acid-defined (CDAA) diet (96-99). Our HFD-induced NASH rat model shows similar results (100). When IL-1α, IL-1β, or IL-1R is deleted, the hepatic injury induced by NASH is attenuated (101, 102). In line with this result, mice deficient of IL-1R antagonist showed severe hepatic fat accumulation and fibrosis after an atherogenic diet feeding, when compared with their wild type littermates (103). Knockout of NLRP3 or addition with pan-caspase inhibitor (VX-166) also exhibits improved hepatic function after the diet induction of NAFLD (95, 104). In human NAFLD and type 2 diabetes patients, increased mRNA expression of the NLRP3 inflammasome components is observed and weight loss management decreases such expression (101, 105).

During NASH, molecular triggers of inflammasomes include DNA, saturated fatty acids and LPS. Csak et al. reported that saturated, but not unsaturated, fatty acids induce the activation of caspase-1 and the release of IL-1β upon stimulation of LPS. They also found that fatty acid-treated hepatocyte is capable of inducing inflammasome activation in hepatic mononuclear cells (105). Another study further confirmed that saturated fatty acid palmitate, but not unsaturated oleate, induces the activation of the NLRP3-ASC inflammasome, leading to caspase-1, IL-1β and IL-18 production. Autophage and increased mROS were also involved in this process (99). Besides that, Kupffer cells are important bridge linking TLR signal transduction and inflammasome activation. Depletion of Kupffer cells markedly decreases the expression of both hepatic and serum level of IL-1β (96). In addition, Kupffer cells promote hepatic steatosis via IL-1β-dependent suppression of peroxisome proliferator-activated receptor alpha (PPARα) activity after chronic HFD feeding (97).

The molecular mechanism of transition from steatosis to NASH is partly explained by a recent study showing that altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of NASH(106). This highlights the importance of maintaining the homeostasis of the gut-liver axis under pathological conditions. Other studies, however, found that inflammasome activity contributes to liver fibrosis and transition from simple steatosis to NASH. By using both knockout mice and knock-in mice expressing constitutive active NLRP3, they found that activation of NLRP3 is required for hepatocyte pyroptosis, inflammation and fibrosis developments in NASH (107, 108). Our recent study also found that bee’s honey is able to attenuate hepatic injury induced by NASH through targeting the TXNIP-NLRP3 pathway (109).

5. Conclusion

In conclusion, inflammasomes are novel protein complexes that modulate a spectrum of exogenous and endogenous danger signals to secrete IL-1β and IL-18. In recent years, research data suggested that activation of inflammasomes contribute to the pathogenesis of type 2 diabetes and obesity (110-113). As a contributor and a direct consequence of metabolic syndrome, the role of inflammasome complexes in the initiation and progression of NAFLD has been extensively studied. However, several key questions remain largely unknown and warrant further investigations:

(1) The role of inflammasomes other than NLRP3 and NLRP6 in the pathogenesis of NASH should be clearly defined;

(2) The importance of the gut-liver axis in liver diseases receives much attention. However, detailed mechanisms that influence the microbiota homeostasis and hepatic inflammation needs further detailed study;

(3) The inter-organs crosstalk during obesity and insulin resistance development needs to be defined. The liver may directly or indirectly “communicate with” adipose tissue, intestine, pancreas, muscles, and the entire circulation system to affect the metabolic status of the body;

(4) Gene polymorphism studies on suitable patient cohorts may help to determine the link between the prevalence of metabolic syndrome and genetics. Also, it should shed light on the early-stage prediction of metabolic diseases.

(5) Identification of selective pharmacological drugs that inhibit inflammasome pathways should provide solid proof of the significance of inflammasomes in the development of metabolic inflammation. For example, glyburide is an anti-diabetic drug directly targeting the NLRP3 inflammasome (111). Development of such drugs may significantly accelerate the clinical therapeutic development against metabolic syndrome and other chronic inflammatory liver diseases.

Additional research information addressing the above questions may not only offer a better understanding of the inflammasome pathways in the liver diseases, particularly in NAFLD/NASH, but it will also hopefully lead to novel and specific therapeutic strategy against obesity-related conditions in the entire body.

6. Acknowledgemen

Supported by the National Natural Science Foundation of China (Grant No. 31300813) and Small Project Fund, The University of Hong Kong.

References

    1. S Mandayam, MM Jamal, TR Morgan: Epidemiology of alcoholic liver disease. Semin Liver Dis 24, 217-232 (2004)

    2. BF Grant, MC Dufour, TC Harford: Epidemiology of alcoholic liver disease. Semin Liver Dis 8, 12-25 (1988)

    3. S Kojima, N Watanabe, M Numata, T Ogawa, S Matsuzaki: Increase in the prevalence of fatty liver in Japan over the past 12 years: analysis of clinical background. J Gastroenterol 38, 954-961 (2003)

    4. SA Harrison, S Torgerson, PH Hayashi: The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am J Gastroenterol 98, 2042-2047 (2003)

    5. JG Fan, GC Farrell: Epidemiology of non-alcoholic fatty liver disease in China. J Hepatol 50 204-210 (2009)

    6. E Bugianesi, N Leone, E Vanni, G Marchesini, F Brunello, P Carucci, A Musso, P De Paolis, L Capussotti, M Salizzoni, M Rizzetto: Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 123, 134-140 (2002)

    7. RS O’shea, S Dasarathy, AJ McCullough: Alcoholic liver disease. Hepatology 51, 307-328 (2010)

    8. S Stewart, D Jones, CP Day: Alcoholic liver disease: new insights into mechanisms and preventative strategies. Trends Mol Med 7, 408-413 (2001)

    9. J Xiao, R Guo, ML Fung, EC Liong, GL Tipoe: Therapeutic approaches to non-alcoholic fatty liver disease: past achievements and future challenges. Hepatobiliary Pancreat Dis Int 12, 125-135 (2013)

    10. M Ganz, G Szabo: Immune and inflammatory pathways in NASH. Hepatol Int 7, 771-781 (2013)

    11. J Xiao, KF So, EC Liong, GL Tipoe: Recent advances in the herbal treatment of non-alcoholic Fatty liver disease. J Tradit Complement Med 3, 88-94 (2013)

    12. H Tilg, AR Moschen: Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52, 1836-1846 (2010)

    13. DG Tiniakos, MB Vos, EM Brunt: Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol 5, 145-171 (2010)

    14. Z Li, S Yang, H Lin, J Huang, PA Watkins, AB Moser, C Desimone, XY Song, AM Diehl: Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 37, 343-350 (2003)

    15. P Banerjee, S Jana, S Chakraborty, S Swarnakar: Inflammation and MMPs in alcohol-induced liver diseases and protective action of antioxidants. Indian J Biochem Biophys 50, 377-386 (2013)

    16. AH Clementi, AM Gaudy, N van Rooijen, RH Pierce, RA Mooney: Loss of Kupffer cells in diet-induced obesity is associated with increased hepatic steatosis, STAT3 signaling, and further decreases in insulin signaling. Biochim Biophys Acta 1792, 1062-1072 (2009)

    17. V Luangrath, MR Brodeur, D Rhainds, L Brissette: Mouse CD36 has opposite effects on LDL and oxidized LDL metabolism in vivo. Arterioscler Thromb Vasc Biol 28, 1290-1295 (2008)

    18. K Fon Tacer, D Kuzman, M Seliskar, D Pompon, D Rozman: TNF-alpha interferes with lipid homeostasis and activates acute and proatherogenic processes. Physiol Genomics 31, 216-227 (2007)

    19. K Fon Tacer, D Pompon, D Rozman: Adaptation of cholesterol synthesis to fasting and TNF-alpha: profiling cholesterol intermediates in the liver, brain, and testis. J Steroid Biochem Mol Biol 121, 619-625 (2010)

    20. M Duvnjak, I Lerotic, N Barsic, V Tomasic, L Virovic Jukic, V Velagic: Pathogenesis and management issues for non-alcoholic fatty liver disease. World J Gastroenterol 13, 4539-4550 (2007)

    21. J Xiao, YP Ching, EC Liong, AA Nanji, ML Fung, GL Tipoe: Garlic-derived S-allylmercaptocysteine is a hepato-protective agent in non-alcoholic fatty liver disease in vivo animal model. Eur J Nutr 52, 179-191 (2013)

    22. J Xiao, EC Liong, YP Ching, RC Chang, ML Fung, AM Xu, KF So, GL Tipoe: Lycium barbarum polysaccharides protect rat liver from non-alcoholic steatohepatitis-induced injury. Nutr Diabetes 3, e81 (2013)

    23. C Zuany-Amorim, J Hastewell, C Walker: Toll-like receptors as potential therapeutic targets for multiple diseases. Nat Rev Drug Discov 1, 797-807 (2002)

    24. CA Rivera, P Adegboyega, N van Rooijen, A Tagalicud, M Allman, M Wallace: Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol 47, 571-579 (2007)

    25. EA Griffiths, LC Duffy, FL Schanbacher, H Qiao, D Dryja, A Leavens, J Rossman, G Rich, D Dirienzo, PL Ogra: In vivo effects of bifidobacteria and lactoferrin on gut endotoxin concentration and mucosal immunity in Balb/c mice. Dig Dis Sci 49, 579-589 (2004)

    26. F Martinon, K Burns, J Tschopp: The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10, 417-426 (2002)

    27. HM Hoffman, JL Mueller, DH Broide, AA Wanderer, RD Kolodner: Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet 29, 301-305 (2001)

    28. ED Boyden, WF Dietrich: Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet 38, 240-244 (2006)

    29. SL Masters, M Gerlic, D Metcalf, S Preston, M Pellegrini, JA O’Donnell, K McArthur, TM Baldwin, S Chevrier, CJ Nowell, LH Cengia, KJ Henley, JE Collinge, DL Kastner, L Feigenbaum, DJ Hilton, WS Alexander, BT Kile, BA Croker: NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. Immunity 37, 1009-1023 (2012)

    30. K Schroder, J Tschopp: The inflammasomes. Cell 140, 821-832 (2010)

    31. JA Kummer, R Broekhuizen, H Everett, L Agostini, L Kuijk, F Martinon, R van Bruggen, J Tschopp: Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response. J Histochem Cytochem 55, 443-452 (2007)

    32. J Minkiewicz, JP de Rivero Vaccari, RW Keane: Human astrocytes express a novel NLRP2 inflammasome. Glia 61, 1113-1121 (2013)

    33. E Benetti, F Chiazza, NS Patel, M Collino: The NLRP3 Inflammasome as a novel player of the intercellular crosstalk in metabolic disorders. Mediators Inflamm 2013, 678627 (2013)

    34. M Haneklaus, LA O’Neill, RC Coll: Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments. Curr Opin Immunol 25, 40-45 (2013)

    35. T Yamazaki, T Ichinohe: Inflammasomes in antiviral immunity: clues for influenza vaccine development. Clin Exp Vaccine Res 3, 5-11 (2014)

    36. E Elinav, T Strowig, AL Kau, J Henao-Mejia, CA Thaiss, CJ Booth, DR Peaper, J Bertin, SC Eisenbarth, JI Gordon, RA Flavell: NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745-757 (2011)

    37. S Normand, A Delanoye-Crespin, A Bressenot, L Huot, T Grandjean, L Peyrin-Biroulet, Y Lemoine, D Hot, M Chamaillard: Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury. Proc Natl Acad Sci U S A 108, 9601-9606 (2011)

    38. M Wlodarska, CA Thaiss, R Nowarski, J Henao-Mejia, JP Zhang, EM Brown, G Frankel, M Levy, MN Katz, WM Philbrick, E Elinav, BB Finlay, RA Flavell: NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 156, 1045-1059 (2014)

    39. Y Wang, M Hasegawa, R Imamura, T Kinoshita, C Kondo, K Konaka, T Suda: PYNOD, a novel Apaf-1/CED4-like protein is an inhibitor of ASC and caspase-1. Int Immunol 16, 777-786 (2004)

    40. SC Eisenbarth, A Williams, OR Colegio, H Meng, T Strowig, A Rongvaux, J Henao-Mejia, CA Thaiss, S Joly, DG Gonzalez, L Xu, LA Zenewicz, AM Haberman, E Elinav, SH Kleinstein, FS Sutterwala, RA Flavell: NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells. Nature 484, 510-513 (2012)

    41. I Jeru, G Le Borgne, E Cochet, H Hayrapetyan, P Duquesnoy, G Grateau, A Morali, T Sarkisian, S Amselem: Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes. Arthritis Rheum 63, 1459-1464 (2011)

    42. GI Vladimer, D Weng, SW Paquette, SK Vanaja, VA Rathinam, MH Aune, JE Conlon, JJ Burbage, MK Proulx, Q Liu, G Reed, JC Mecsas, Y Iwakura, J Bertin, JD Goguen, KA Fitzgerald, E Lien: The NLRP12 inflammasome recognizes Yersinia pestis. Immunity 37, 96-107 (2012)

    43. MA Ataide, WA Andrade, DS Zamboni, D Wang, C Souza Mdo, BS Franklin, S Elian, FS Martins, D Pereira, G Reed, KA Fitzgerald, DT Golenbock, RT Gazzinelli: Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection. PLoS Pathog 10, e1003885 (2014)

    44. IC Allen, JE Wilson, M Schneider, JD Lich, RA Roberts, JC Arthur, RM Woodford, BK Davis, JM Uronis, HH Herfarth, C Jobin, AB Rogers, JP Ting: NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-kappaB signaling. Immunity 36, 742-754 (2012)

    45. EA Miao, DP Mao, N Yudkovsky, R Bonneau, CG Lorang, SE Warren, IA Leaf, A Aderem: Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc Natl Acad Sci U S A 107, 3076-3080 (2010)

    46. Y Qu, S Misaghi, A Izrael-Tomasevic, K Newton, LL Gilmour, M Lamkanfi, S Louie, N Kayagaki, J Liu, L Komuves, JE Cupp, D Arnott, D Monack, VM Dixit: Phosphorylation of NLRC4 is critical for inflammasome activation. Nature 490, 539-542 (2012)

    47. S Suzuki, L Franchi, Y He, R Munoz-Planillo, H Mimuro, T Suzuki, C Sasakawa, G Nunez: Shigella type III secretion protein MxiI is recognized by Naip2 to induce Nlrc4 inflammasome activation independently of Pkcdelta. PLoS Pathog 10, e1003926 (2014)

    48. DA Muruve, V Petrilli, AK Zaiss, LR White, SA Clark, PJ Ross, RJ Parks, J Tschopp: The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 452, 103-107 (2008)

    49. V Hornung, A Ablasser, M Charrel-Dennis, F Bauernfeind, G Horvath, DR Caffrey, E Latz, KA Fitzgerald: AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458, 514-518 (2009)

    50. VA Rathinam, Z Jiang, SN Waggoner, S Sharma, LE Cole, L Waggoner, SK Vanaja, BG Monks, S Ganesan, E Latz, V Hornung, SN Vogel, E Szomolanyi-Tsuda, KA. Fitzgerald: The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol 11, 395-402 (2010)

    51. R Hanamsagar, A Aldrich, T Kielian: Critical role for the AIM2 inflammasome during acute CNS bacterial infection. J Neurochem 129, 704-711 (2014)

    52. P Menu, A Mayor, R Zhou, A Tardivel, H Ichijo, K Mori, J Tschopp: ER stress activates the NLRP3 inflammasome via an UPR-independent pathway. Cell Death Dis 3, e261 (2012)

    53. AG Lerner, JP Upton, PV Praveen, R Ghosh, Y Nakagawa, A Igbaria, S Shen, V Nguyen, BJ Backes, M Heiman, N Heintz, P Greengard, S Hui, Q Tang, A Trusina, SA Oakes, FR Papa: IRE1alpha induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab 16, 250-264 (2012)

    54. CM Oslowski, T Hara, B O’sullivan-Murphy, K Kanekura, S Lu, M Hara, S Ishigaki, LJ Zhu, E Hayashi, ST Hui, D Greiner, RJ Kaufman, R Bortell, F Urano: Thioredoxin-interacting protein mediates ER stress-induced beta cell death through initiation of the inflammasome. Cell Metab 16, 265-273 (2012)

    55. J Xiao, Y Zhu, Y Liu, GL Tipoe, F Xing, KF So: Lycium barbarum polysaccharide attenuates alcoholic cellular injury through TXNIP-NLRP3 inflammasome pathway. Int J Biol Macromol 69, 73-78 (2014)

    56. SL Masters, A Dunne, SL Subramanian, RL Hull, GM Tannahill, FA Sharp, C Becker, L Franchi, E Yoshihara, Z Chen, N Mullooly, LA Mielke, J Harris, RC Coll, KH Mills, KH Mok, P Newsholme, G Nunez, J Yodoi, SE Kahn, EC Lavelle, LA O’Neill: Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol 11, 897-904 (2010)

    57. T Murakami, J Ockinger, J Yu, V Byles, A McColl, AM Hofer, T Horng: Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci U S A 109, 11282-11287 (2012)

    58. GS Lee, N Subramanian, AI Kim, I Aksentijevich, R Goldbach-Mansky, DB Sacks, RN Germain, DL Kastner, JJ Chae: The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 492, 123-127 (2012)

    59. V Compan, A Baroja-Mazo, G Lopez-Castejon, AI Gomez, CM Martinez, D Angosto, MT Montero, AS Herranz, E Bazan, D Reimers, V Mulero, P Pelegrin: Cell volume regulation modulates NLRP3 inflammasome activation. Immunity 37, 487-500 (2012)

    60. Z Zhong, Y Zhai, S Liang, Y Mori, R Han, FS Sutterwala, L Qiao: TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat Commun 4, 1611 (2013)

    61. K Labbe, CR McIntire, K Doiron, PM Leblanc, M Saleh: Cellular inhibitors of apoptosis proteins cIAP1 and cIAP2 are required for efficient caspase-1 activation by the inflammasome. Immunity 35, 897-907 (2011)

    62. JE Vince, WW Wong, I Gentle, KE Lawlor, R Allam, L O’Reilly, K Mason, O Gross, S Ma, G Guarda, H Anderton, R Castillo, G Hacker, J Silke, J. Tschopp: Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity 36, 215-227 (2012)

    63. L Bossaller, PI Chiang, C Schmidt-Lauber, S Ganesan, WJ Kaiser, VA Rathinam, ES Mocarski, D Subramanian, DR Green, N Silverman, KA Fitzgerald, A Marshak-Rothstein, E Latz: Cutting edge: FAS (CD95) mediates noncanonical IL-1beta and IL-18 maturation via caspase-8 in an RIP3-independent manner. J Immunol 189, 5508-5512 (2012)

    64. J Maelfait, E Vercammen, S Janssens, P Schotte, M Haegman, S Magez, R Beyaert: Stimulation of Toll-like receptor 3 and 4 induces interleukin-1beta maturation by caspase-8. J Exp Med 205, 1967-1973 (2008)

    65. SI Gringhuis, TM Kaptein, BA Wevers, B Theelen, M van der Vlist, T Boekhout, TB Geijtenbeek: Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1beta via a noncanonical caspase-8 inflammasome. Nat Immunol 13, 246-254 (2012)

    66. H Wen, EA Miao, JP Ting: Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity 39, 432-441 (2013)

    67. AR Shenoy, DA Wellington, P Kumar, H Kassa, CJ Booth, P Cresswell, JD MacMicking: GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals. Science 336, 481-485 (2012)

    68. B Lu, T Nakamura, K Inouye, J Li, Y Tang, P Lundback, SI Valdes-Ferrer, PS Olofsson, T Kalb, J Roth, Y Zou, H Erlandsson-Harris, H Yang, JP Ting, H Wang, U Andersson, DJ Antoine, SS Chavan, GS Hotamisligil, KJ Tracey: Novel role of PKR in inflammasome activation and HMGB1 release. Nature 488, 670-674 (2012)

    69. Y He, L Franchi, G Nunez: The protein kinase PKR is critical for LPS-induced iNOS production but dispensable for inflammasome activation in macrophages. Eur J Immunol 43, 1147-1152 (2013)

    70. W Yan, Y Chang, X Liang, JS Cardinal, H Huang, SH Thorne, SP Monga, DA Geller, MT Lotze, A Tsung: High-mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases. Hepatology 55, 1863-1875 (2012)

    71. A Watanabe, MA Sohail, DA Gomes, A Hashmi, J Nagata, FS Sutterwala, S Mahmood, MN Jhandier, Y Shi, RA Flavell, WZ Mehal: Inflammasome-mediated regulation of hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 296, G1248-1257 (2009)

    72. AB Imaeda, A Watanabe, MA Sohail, S Mahmood, M Mohamadnejad, FS Sutterwala, RA Flavell, WZ Mehal: Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J Clin Invest 119, 305-314 (2009)

    73. R Rawat, TV Cohen, B Ampong, D Francia, A Henriques-Pons, EP Hoffman, K Nagaraju: Inflammasome up-regulation and activation in dysferlin-deficient skeletal muscle. Am J Pathol 176, 2891-2900 (2010)

    74. T Manigold, U Bocker, J Chen, J Gundt, P Traber, MV Singer, S Rossol: Hepatitis B core antigen is a potent inductor of interleukin-18 in peripheral blood mononuclear cells of healthy controls and patients with hepatitis B infection. J Med Virol 71, 31-40 (2003)

    75. J Zhen, L Zhang, J Pan, S Ma, X Yu, X Li, S Chen, W Du: AIM2 mediates inflammation-associated renal damage in hepatitis B virus-associated glomerulonephritis by regulating caspase-1, IL-1beta, and IL-18. Mediators Inflamm 2014, 190860 (2014)

    76. W Du, J Zhen, Z Zheng, S Ma, S Chen: Expression of AIM2 is high and correlated with inflammation in hepatitis B virus associated glomerulonephritis. J Inflamm 10, 37 (2013)

    77. A Antonelli, C Ferri, SM Ferrari, S De Marco, A Di Domenicantonio, M Centanni, C Pupilli, E Villa, F Menichetti, P Fallahi: Interleukin-1beta, C-x-C motif ligand 10, and interferon-gamma serum levels in mixed cryoglobulinemia with or without autoimmune thyroiditis. J Interferon Cytokine Res 30, 835-842 (2010)

    78. D Burdette, A Haskett, L Presser, S McRae, J Iqbal, G Waris: Hepatitis C virus activates interleukin-1beta via caspase-1-inflammasome complex. J Gen Virol 93, 235-246 (2012)

    79. AA Negash, HJ Ramos, N Crochet, DT Lau, B Doehle, N Papic, DA Delker, J Jo, A Bertoletti, CH Hagedorn, M Gale, Jr.: IL-1beta production through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease. PLoS Pathog 9, e1003330 (2013)

    80. RJ Fontana: Acute liver failure including acetaminophen overdose. Med Clin North Am 92, 761-794, viii (2008)

    81. JJ Maher: DAMPs ramp up drug toxicity. J Clin Invest 119, 246-249 (2009)

    82. DM Dambach, LM Watson, KR Gray, SK Durham, DL Laskin: Role of CCR2 in macrophage migration into the liver during acetaminophen-induced hepatotoxicity in the mouse. Hepatology 35, 1093-1103 (2002)

    83. CJ Chen, H Kono, D Golenbock, G Reed, S Akira, KL Rock: Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat Med 13, 851-856 (2007)

    84. T Ishibe, A Kimura, Y Ishida, T Takayasu, T Hayashi, K Tsuneyama, K Matsushima, I Sakata, N Mukaida, T Kondo: Reduced acetaminophen-induced liver injury in mice by genetic disruption of IL-1 receptor antagonist. Lab Invest 89, 68-79 (2009)

    85. LP James, HC Farrar, TL Darville, JE Sullivan, TG Givens, GL Kearns, GS Wasserman, PM Simpson, JA Hinson: Elevation of serum interleukin 8 levels in acetaminophen overdose in children and adolescents. Clin Pharmacol Ther 70, 280-286 (2001)

    86. CD Williams, A Farhood, H Jaeschke: Role of caspase-1 and interleukin-1beta in acetaminophen-induced hepatic inflammation and liver injury. Toxicol Appl Pharmacol 247, 169-178 (2010)

    87. G Szabo, T Csak: Inflammasomes in liver diseases. J Hepatol 57, 642-654 (2012)

    88. H Jaeschke: Reactive oxygen and mechanisms of inflammatory liver injury: Present concepts. J Gastroenterol Hepatol 26, 173-179 (2011)

    89. H Huang, HW Chen, J Evankovich, W Yan, BR Rosborough, GW Nace, Q Ding, P Loughran, D Beer-Stolz, TR Billiar, CT Esmon, A Tsung: Histones activate the NLRP3 inflammasome in Kupffer cells during sterile inflammatory liver injury. J Immunol, 191, 2665-2679 (2013)

    90. P Zhu, L Duan, J Chen, A Xiong, Q Xu, H Zhang, F Zheng, Z Tan, F Gong, M Fang: Gene silencing of NALP3 protects against liver ischemia-reperfusion injury in mice. Hum Gene Ther 22, 853-864 (2011)

    91. D Takeuchi, H Yoshidome, A Kato, H Ito, F Kimura, H Shimizu, M Ohtsuka, Y Morita, M Miyazaki: Interleukin 18 causes hepatic ischemia/reperfusion injury by suppressing anti-inflammatory cytokine expression in mice. Hepatology 39, 699-710 (2004)

    92. A Tsung, RA Hoffman, K Izuishi, ND Critchlow, A Nakao, MH Chan, MT Lotze, DA Geller, TR Billiar: Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells. J Immunol 175, 7661-7668 (2005)

    93. ZM Bamboat, VP Balachandran, LM Ocuin, H Obaid, G Plitas, RP DeMatteo: Toll-like receptor 9 inhibition confers protection from liver ischemia-reperfusion injury. Hepatology 51, 621-632 (2010)

    94. SL Valles, AM Blanco, I Azorin, R Guasch, M Pascual, MJ Gomez-Lechon, J Renau-Piqueras, C Guerri: Chronic ethanol consumption enhances interleukin-1-mediated signal transduction in rat liver and in cultured hepatocytes. Alcohol Clin Exp Res 27, 1979-1986 (2003)

    95. J Petrasek, S Bala, T Csak, D Lippai, K Kodys, V Menashy, M Barrieau, SY Min, EA Kurt-Jones, G Szabo: IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest 122, 3476-3489 (2012)

    96. K Miura, Y Kodama, S Inokuchi, B Schnabl, T Aoyama, H Ohnishi, JM Olefsky, DA Brenner, E Seki: Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology 139, 323-334.e7 (2010)

    97. R Stienstra, F Saudale, C Duval, S Keshtkar, JE Groener, N van Rooijen, B Staels, S Kersten, M Muller: Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity. Hepatology 51, 511-522 (2010)

    98. B Vandanmagsar, YH Youm, A Ravussin, JE Galgani, K Stadler, RL Mynatt, E Ravussin, JM Stephens, VD Dixit: The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17, 179-188 (2011)

    99. H Wen, D Gris, Y Lei, S Jha, L Zhang, MT Huang, WJ Brickey, JP Ting: Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 12, 408-415 (2011)

    100. J Xiao, F Xing, J Huo, ML Fung, EC Liong, YP Ching, A Xu, RC Chang, KF So, GL Tipoe: Lycium barbarum polysaccharides therapeutically improve hepatic functions in non-alcoholic steatohepatitis rats and cellular steatosis model. Sci Rep 4, 5587 (2014)

    101. B de Roos, V Rungapamestry, K Ross, G Rucklidge, M Reid, G Duncan, G Horgan, S Toomey, J Browne, CE Loscher, KH Mills, HM Roche: Attenuation of inflammation and cellular stress-related pathways maintains insulin sensitivity in obese type I interleukin-1 receptor knockout mice on a high-fat diet. Proteomics 9, 3244-3256 (2009)

    102. Y Kamari, A Shaish, E Vax, S Shemesh, M Kandel-Kfir, Y Arbel, S Olteanu, I Barshack, S Dotan, E Voronov, CA Dinarello, RN Apte, D Harats: Lack of interleukin-1alpha or interleukin-1beta inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. J Hepatol 55, 1086-1094 (2011)

    103. K Isoda, S Sawada, M Ayaori, T Matsuki, R Horai, Y Kagata, K Miyazaki, M Kusuhara, M Okazaki, O Matsubara, Y Iwakura, F Ohsuzu: Deficiency of interleukin-1 receptor antagonist deteriorates fatty liver and cholesterol metabolism in hypercholesterolemic mice. J Biol Chem 280, 7002-7009 (2005)

    104. RP Witek, WC Stone, FG Karaca, WK Syn, TA Pereira, KM Agboola, A Omenetti, Y Jung, V Teaberry, SS Choi, CD Guy, J Pollard, P Charlton, AM Diehl: Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis. Hepatology 50, 1421-1430 (2009)

    105. T Csak, M Ganz, J Pespisa, K Kodys, A Dolganiuc, G Szabo: Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology 54, 133-144 (2011)

    106. J Henao-Mejia, E Elinav, C Jin, L Hao, WZ Mehal, T Strowig, CA Thaiss, AL Kau, SC Eisenbarth, MJ Jurczak, JP. Camporez, GI Shulman, JI Gordon, HM Hoffman, RA Flavell: Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179-185 (2012)

    107. A Wree, A Eguchi, MD McGeough, CA Pena, CD Johnson, A Canbay, HM Hoffman, AE Feldstein: NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology 59, 898-910 (2014)

    108. A Wree, MD McGeough, CA Pena, M Schlattjan, H Li, ME Inzaugarat, K Messer, A Canbay, HM Hoffman, AE Feldstein: NLRP3 inflammasome activation is required for fibrosis development in NAFLD. J Mol Med 92, 1069-1082 (2014)

    109. J Xiao, Y Liu, F Xing, TM Leung, EC Liong, GL Tipoe: Bee’s honey attenuates non-alcoholic steatohepatitis-induced hepatic injury through the regulation of thioredoxin-interacting protein-NLRP3 inflammasome pathway. Eur J Nutr (2015)

    110. J Jager, T Gremeaux, M Cormont, Y Le Marchand-Brustel, JF Tanti: Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology 148, 241-251 (2007)

    111. CM Larsen, M Faulenbach, A Vaag, A Volund, JA Ehses, B Seifert, T Mandrup-Poulsen, MY Donath: Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 356, 1517-1526 (2007)

    112. R Stienstra, LA Joosten, T Koenen, B van Tits, JA van Diepen, SA van den Berg, PC Rensen, PJ Voshol, G Fantuzzi, A Hijmans, S Kersten, M Muller, WB van den Berg, N van Rooijen, M Wabitsch, BJ Kullberg, JW van der Meer, T Kanneganti, CJ Tack, MG Netea: The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab 12, 593-605 (2010)

    113. M Lamkanfi, JL Mueller, AC Vitari, S Misaghi, A Fedorova, K Deshayes, WP Lee, HM Hoffman, VM Dixit: Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J Cell Biol 187, 61-70 (2009)

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Jia Xiao, George L. Tipoe. Inflammasomes in non-alcoholic fatty liver disease. Frontiers in Bioscience-Landmark. 2016. 21(4); 683-695.