Hepatic nucleotide binding oligomerization domain<b>‐</b>like receptors pyrin domain‐containing 3 inflammasomes are associated with the histologic severity of non‐alcoholic fatty liver disease

Mitsuyoshi, Hironori; Yasui, Kohichiroh; Hara, Tasuku; Taketani, Hiroyoshi; Ishiba, Hiroshi; Okajima, Akira; Seko, Yuya; Umemura, Atsushi; Nishikawa, Taichiro; Yamaguchi, Kanji; Moriguchi, Michihisa; Minami, Masahito; Itoh, Yoshito

doi:10.1111/hepr.12883

Cited by 23 publications

(16 citation statements)

References 43 publications

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“…The patatin-like phospholipase domain-containing 3 (PNPLA3) is a triacylglycerol lipase, which mediates triacylglycerol hydrolysis in adipocytes. The PNPLA3 missense variant rs738409 (Ile148Met) (C > G), causing loss of function, is associated with hyperexpression of the NLRP3 inflammasome, leading to increased serum levels of IL-1β and IL18 ( Mitsuyoshi et al, 2017 ). It is known that many viruses and among them SARS-CoV-2, are directly able to induce activation of the NRLP3 inflammasome leading to the cytokines storm probably causing most fatal outcomes ( Farag et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

PNPLA3 and TLL-1 Polymorphisms as Potential Predictors of Disease Severity in Patients With COVID-19

Grimaudo

Amodio

Pipitone

et al. 2021

Front. Cell Dev. Biol.

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Albeit the pathogenesis of COVID-19 remains unclear, host’s genetic polymorphisms in genes involved in infection and reinfection, inflammation, or immune stimulation could play a role in determining the course and outcome. We studied in the early phase of pandemic consecutive patients (N = 383) with SARS-CoV-2 infection, whose subsequent clinical course was classified as mild or severe, the latter being characterized by admission to intensive therapy unit or death. Five host gene polymorphisms (MERTK rs4374383, PNPLA3 rs738409, TLL-1 rs17047200, IFNL3 rs1297860, and INFL4 rs368234815) were assessed by using whole nucleic acids extracted from nasopharyngeal swabs. Specific protease cleavage sites of TLL-1 on the SARS-CoV-2 Spike protein were predicted in silico. Male subjects and older patients were significantly at higher risk for a severe outcome (p = 0.02 and p < 0.001, respectively). By considering patients ≤65 years, after adjusting for potential confounding due to sex, an increased risk of severe outcome was found in subjects with the GG genotype of PNPLA3 (adj-OR: 4.69; 95% CI = 1.01–22.04) or TT genotype of TLL-1 (adj-OR=9.1; 95% CI = 1.45–57.3). In silico evaluation showed that TLL-1 is potentially involved in the Spike protein cleavage which is essential for viral binding and entry into the host cells using the host receptor angiotensin-converting enzyme 2 (ACE2). Subjects carrying a GG genotype in PNPLA3 gene might have a constitutive upregulation of the NLRP3 inflammasome and be more prone to tissue damage when infected by SARS-CoV-2. The TT genotype in TLL-1 gene might affect its protease activity on the SARS-CoV-2 Spike protein, enhancing the ability to infect or re-infect host’s cells. The untoward effect of these variants on disease course is evident in younger patients due to the relative absence of comorbidities as determinants of prognosis. In the unresolved pathogenetic scenery of COVID-19, the identification of genetic variants associates with more prolonged course or with a severe outcome of infection would support the development of predictive tools useful to stratify subjects by risk class at presentation. Moreover, the individuation of key genes could contribute to a better understanding of the pathways involved in the pathogenesis, giving the basis for rational therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

PNPLA3 and TLL-1 Polymorphisms as Potential Predictors of Disease Severity in Patients With COVID-19

Grimaudo

Amodio

Pipitone

et al. 2021

Front. Cell Dev. Biol.

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“…Recently, NLRP3 inflammasome is reported to be an important contributor to the development of NAFLD [24–26]. NLRP3 inflammasome can be activated by metabolic danger signals, such as free fatty acids, oxidized LDL, cholesterol crystals, and uric acid [27–30].…”

Section: Discussionmentioning

confidence: 99%

Compound C Protects Mice from HFD-Induced Obesity and Nonalcoholic Fatty Liver Disease

Wang

Liu

Yuan

et al. 2019

International Journal of Endocrinology

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Objectives. The aim of this study was to investigate the effects of compound C on an in vivo mouse model of high-fat diet- (HFD-) induced obesity and hepatosteatosis. Methods. C57BL/6 mice were fed with a standard diet (n = 5) for 16 weeks and then injected saline once a day for 4 weeks as the normal chow group. Mice (n = 10) were fed with HFD for 16 weeks to induce obesity and hepatosteatosis and then divided into two groups: HFD + vehicle group injected with the vehicle solution (saline) and HFD + compound C group injected with compound C in saline (5 mg/kg i.p., once a day) for 4 weeks. Liver histology was observed. The expression levels of genes related to lipid metabolism and proinflammation in liver tissue were examined. NLRP3 inflammasome expression in liver tissue was detected by the western blot assay. HepG2 cells were pretreated with compound C and/or AICAR for 1 h and then treated with palmitic acid (PA) for 3 h. The cells were collected, and mRNA levels were determined. Results. There was a significant reduction in body-weight gain and daily food intake in the HFD + compound C group compared with the HFD + vehicle group (p<0.05). The glucose tolerance test (GTT) and insulin tolerance test (ITT) showed that compound C alleviated insulin resistance. Histology analysis showed a significant reduction of hepatic steatosis by compound C. Compound C also significantly decreased fatty acid synthesis genes, while increased fatty acid oxidation genes. Furthermore, compound C significantly reduced the expression of proinflammatory markers and NLRP3 inflammasome (p<0.05). Compound C enhanced mRNA levels of SOD1, SOD2, catalase, GPx1, and GPx4 and reduced the p-AMPK/AMPK ratio, which were stimulated by palmitic acid (PA). The effect was enhanced by AICAR. Conclusion. Our data suggest that compound C is a potent NAFLD suppressor and an attractive therapeutic target for hepatic steatosis and related metabolic disorders.

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“…Secondly, the activation of NLRP3 inflammasome upon the sensation of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) causes the cleavage of caspase-1, which subsequently cleaves pro-IL-1β and pro-IL-18 into their active forms, IL-1β and IL-18 [ 5 , 6 ]. NLRP3 inflammasome was reported to be associated with the histologic severity of NAFLD in patients [ 7 ], and NLRP3 plays a crucial role in the pathogenesis of NASH induced by methionine choline-deficient diet (MCD) [ 8 ], high-fat diet (HFD) [ 9 ], and high fat-cholesterol-sugar diet (HF-HC-HSD) [ 10 , 11 ]. NLRP3 inflammasome activation correlated with liver steatosis, inflammation, fibrosis, and tumorigenesis [ 10 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Red yeast rice ameliorates non-alcoholic fatty liver disease through inhibiting lipid synthesis and NF-κB/NLRP3 inflammasome-mediated hepatic inflammation in mice

2022

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Background Red yeast rice (RYR), a nutraceutical with a profound cholesterol-lowering effect, was found to attenuate non-alcoholic fatty liver disease (NAFLD) in mice. Despite monacolin K in RYR being a specific inhibitor of hydroxymethylglutaryl-coenzyme A reductase (HMCGR), the mechanisms underlying the protective effects of RYR against NAFLD are not fully elucidated. Methods Using a mouse model of high-fat diet (HFD) feeding and a cellular model of HepG2 cells challenged by lipopolysaccharide (LPS) and palmitic acid (PA), the possible molecular mechanisms were exploited in the aspects of NF-κB/NLRP3 inflammasome and mTORC1-SREBPs signaling pathways by examining the relevant gene/protein expressions. Subsequently, the correlation between these two signals was also verified using cellular experiments. Results RYR ameliorated lipid accumulation and hepatic inflammation in vivo and in vitro. RYR improved lipid metabolism through modulating mTORC1-SREBPs and their target genes related to triglyceride and cholesterol synthesis. Furthermore, RYR suppressed hepatic inflammation by inhibiting the NF-κB/NLRP3 inflammasome signaling. Interestingly, the treatment with RYR or MCC950, a specific NLRP3 inhibitor, resulted in the reduced lipid accumulation in HepG2 cells challenged by LPS plus PA, suggesting that the inhibitory effects of RYR on NLRP3 inflammasome-mediated hepatic inflammation may partially, in turn, contribute to the lipid-lowering effect of RYR. Conclusions The modulation of NF-κB/NLRP3 inflammasome and lipid synthesis may contribute to the ameliorative effects of RYR against HFD-induced NAFLD.

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Hepatic nucleotide binding oligomerization domain‐like receptors pyrin domain‐containing 3 inflammasomes are associated with the histologic severity of non‐alcoholic fatty liver disease

Abstract: The NLRP3 inflammasomes are primed in the liver, influenced by adiponutrin genotypes, and activated in Kupffer cells and/or macrophages in NAFLD, leading to histological progression through IL-1β and IL-18 production.

Cited by 23 publications

References 43 publications

PNPLA3 and TLL-1 Polymorphisms as Potential Predictors of Disease Severity in Patients With COVID-19

PNPLA3 and TLL-1 Polymorphisms as Potential Predictors of Disease Severity in Patients With COVID-19

Compound C Protects Mice from HFD-Induced Obesity and Nonalcoholic Fatty Liver Disease

Red yeast rice ameliorates non-alcoholic fatty liver disease through inhibiting lipid synthesis and NF-κB/NLRP3 inflammasome-mediated hepatic inflammation in mice

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