title: Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation.
abstract: Inflammasome activation initiates the development of many inflammatory diseases, including obesity and type 2 diabetes. Therefore, agents that target discrete activation steps could represent very important drugs. We reported previously that ILG, a chalcone from Glycyrrhiza uralensis, inhibits LPS-induced NF-κB activation. Here, we show that ILG potently inhibits the activation of NLRP3 inflammasome, and the effect is independent of its inhibitory potency on TLR4. The inhibitory effect of ILG was stronger than that of parthenolide, a known inhibitor of the NLRP3 inflammasome. GL, a triterpenoid from G. uralensis, had similar inhibitory effects on NLRP3 activity, but high concentrations of GL were required. In contrast, activation of the AIM2 inflammasome was inhibited by GL but not by ILG. Moreover, GL inhibited NLRP3- and AIM2-activated ASC oligomerization, whereas ILG inhibited NLRP3-activated ASC oligomerization. Low concentrations of ILG were highly effective in IAPP-induced IL-1β production compared with the sulfonylurea drug glyburide. In vivo analyses revealed that ILG potently attenuated HFD-induced obesity, hypercholesterolemia, and insulin resistance. Furthermore, ILG treatment improved HFD-induced macrovesicular steatosis in the liver. Finally, ILG markedly inhibited diet-induced adipose tissue inflammation and IL-1β and caspase-1 production in white adipose tissue in ex vivo culture. These results suggest that ILG is a potential drug target for treatment of NLRP3 inflammasome-associated inflammatory diseases.
authors.affiliation: Toyama Prefectural Institute for Pharmaceutical Research, Toyama, Japan; Departments of Immunobiology and Pharmacological Genetics.
authors.forename: Hiroe
authors.initials: H
authors.lastname: Honda
authors.affiliation: Departments of Immunobiology and Pharmacological Genetics, Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology, Saitama, Japan; takatsuk@med.u-toyama.ac.jp ynagai@med.u-toyama.ac.jp.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nagai
authors.affiliation: Toyama Prefectural Institute for Pharmaceutical Research, Toyama, Japan;
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsunaga
authors.affiliation: Departments of Immunobiology and Pharmacological Genetics, Teika Pharmaceutical, Toyama, Japan; and.
authors.forename: Naoki
authors.initials: N
authors.lastname: Okamoto
authors.affiliation: Departments of Immunobiology and Pharmacological Genetics.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Diagnostic Pathology, and.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.affiliation: Department of Natural Products Chemistry, School of Pharmacy, Iwate Medical University, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Natural Products Chemistry, School of Pharmacy, Iwate Medical University, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Fujii
authors.affiliation: Departments of Immunobiology and Pharmacological Genetics.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikutani
authors.affiliation: Departments of Immunobiology and Pharmacological Genetics.
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Hirai
authors.affiliation: Immunology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Japan;
authors.forename: Atsushi
authors.initials: A
authors.lastname: Muraguchi
authors.affiliation: Toyama Prefectural Institute for Pharmaceutical Research, Toyama, Japan; Departments of Immunobiology and Pharmacological Genetics, takatsuk@med.u-toyama.ac.jp ynagai@med.u-toyama.ac.jp.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takatsu
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D047188:Chalcones / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D005905:Glyburide / Q000494:pharmacology / Q000627:therapeutic use; D029882:Glycyrrhiza uralensis / Q000737:chemistry*; D019695:Glycyrrhizic Acid / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy; D058847:Inflammasomes / Q000187:drug effects*; D007249:Inflammation / Q000517:prevention & control*; D007333:Insulin Resistance; D053583:Interleukin-1beta / Q000096:biosynthesis; D058228:Islet Amyloid Polypeptide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009765:Obesity / Q000188:drug therapy / Q000517:prevention & control; D013047:Specific Pathogen-Free Organisms
chemical_list: C540422:Aim2 protein, mouse; D000893:Anti-Inflammatory Agents; D002352:Carrier Proteins; D047188:Chalcones; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D058228:Islet Amyloid Polypeptide; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D019695:Glycyrrhizic Acid; C040920:isoliquiritigenin; D005905:Glyburide
keywords: AIM2; IL-1β; caspase-1; diabetes; glycyrrhizin; obesity