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

Mitsuyoshi H, Yasui K, Hara T et al.

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

Hepatology research : the official journal of the Japan Society of Hepatology. Feb 2017.

To examine the role of nucleotide binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in the development of nonalcoholic fatty liver disease (NAFLD).Levels of mRNAs encoding NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD) (ASC), procaspase-1, interleukin (IL)-1β, and IL-18 were quantified by RT-PCR 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 ELISA and liver tissue caspase-1 expression by immunostaining.Hepatic NLRP3, procaspase-1, IL-1β, and IL-18 mRNAs 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 (NAS). 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, NAS 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.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. (250 words).