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

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.

• Authors: 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
• Journal: Hepatology research : the official journal of the Japan Society of Hepatology (Hepatol Res) Vol. 47 Issue 13 Pg. 1459-1468 (Dec 2017) ISSN: 1386-6346 [Print] Netherlands
• PMID: 28245087 (Publication Type: Journal Article)
• Copyright: © 2017 The Japan Society of Hepatology.