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

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

doi:10.1111/hepr.12883

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

Hepatol Res. 2017 Dec;47(13):1459-1468. doi: 10.1111/hepr.12883. Epub 2017 Mar 29.

Affiliation

¹ Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

PMID: 28245087
DOI: 10.1111/hepr.12883

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.

Keywords: NLRP3 inflammasome; adiponutrin; non-alcoholic fatty liver disease.