title: 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: OBJECTIVE
  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.
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Mitsuyoshi
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Kohichiroh
authors.initials: K
authors.lastname: Yasui
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Hara
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Taketani
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishiba
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Okajima
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Seko
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Umemura
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Taichiro
authors.initials: T
authors.lastname: Nishikawa
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Kanji
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Michihisa
authors.initials: M
authors.lastname: Moriguchi
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Minami
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Itoh
keywords: NLRP3 inflammasome; adiponutrin; non-alcoholic fatty liver disease