Hepatic nucleotide binding oligomerization domain‐like receptors pyrin domain‐containing 3 inflammasomes are associated with the histologic severity of non‐alcoholic fatty liver disease. Issue 13 (29th March 2017)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Hepatology research. Volume 47:Issue 13(2017)
• Page Start: 1459
• Page End: 1468
• Publication Date: 2017-03-29
• Subjects: adiponutrin -- NLRP3 inflammasome -- non‐alcoholic fatty liver disease; Liver -- Diseases -- Periodicals; Liver Diseases -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1111/hepr.12883
• Languages: English
• ISSNs: 1386-6346

Abstract

Abstract: Aim: To examine the role of nucleotide binding oligomerization domain‐ like receptor family pyrin domain‐ containing 3 (NLRP3) inflammasomes in the development of non‐alcoholic fatty liver disease (NAFLD). Methods: Levels of mRNAs encoding NLRP3, apoptosis‐ associated speck‐ like protein containing a caspase recruitment domain, procaspase‐ 1, interleukin (IL)‐ 1β, and IL‐ 18 were quantified by real‐time polymerase chain reaction in 91 liver samples and 37 blood samples from biopsy‐ proven patients with NAFLD. Adiponutrin (also called PNPLA3) polymorphisms (rs738409, C > G) were determined in 74 samples by genotyping assays. Serum IL‐ 1β and IL‐ 18 levels were measured by enzyme‐linked immunosorbent assay and liver tissue caspase‐ 1 expression by immunostaining. Results: Hepatic NLRP3, procaspase‐ 1, IL‐ 1β, and IL‐ 18 mRNA levels were significantly higher in NAFLD patients than in controls and were significantly associated with adiponutrin G alleles. Blood procaspase‐ 1 mRNA was significantly higher in NAFLD patients than in healthy controls. Hepatic procaspase‐ 1 and IL‐ 1β mRNA levels correlated significantly with lobular inflammation, hepatocyte ballooning, and NAFLD activity score. Serum IL‐ 18 levels were significantly higher in NAFLD patients than in controls, while IL‐ 1β levels were non‐ significantly higher. Serum IL‐ 1β and IL‐ 18 concentrations correlated significantly with steatosis, NAFLD activity score, and transaminase levels. Serum IL‐ 1β levels were significantly associated with adiponutrin G alleles. Scattered caspase‐ 1‐ positive cells were present in portal tracts and inflammatory foci and around ballooning hepatocytes. Immunofluorescence staining showed that caspase‐1 colocalized with the macrophage marker CD68. Conclusions: 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.