Deletion of Nardilysin Prevents the Development of Steatohepatitis and Liver Fibrotic Changes

Abstract

Nonalcoholic steatohepatitis (NASH) is an inflammatory form of nonalcoholic fatty liver disease that progresses to liver cirrhosis. It is still unknown how only limited patients with fatty liver develop NASH. Tumor necrosis factor (TNF)-α is one of the key molecules in initiating the vicious circle of inflammations. Nardilysin (N-arginine dibasic convertase; Nrd1), a zinc metalloendopeptidase of the M16 family, enhances ectodomain shedding of TNF-α, resulting in the activation of inflammatory responses. In this study, we aimed to examine the role of Nrd1 in the development of NASH. Nrd1+/+ and Nrd1−/− mice were fed a control choline-supplemented amino acid-defined (CSAA) diet or a choline-deficient amino acid-defined (CDAA) diet. Fatty deposits were accumulated in the livers of both Nrd1+/+ and Nrd1−/− mice by the administration of the CSAA or CDAA diets, although the amount of liver triglyceride in Nrd1−/− mice was lower than that in Nrd1+/+ mice. Serum alanine aminotransferase levels were increased in Nrd1+/+ mice but not in Nrd1−/− mice fed the CDAA diet. mRNA expression of inflammatory cytokines were decreased in Nrd1−/− mice than in Nrd1+/+ mice fed the CDAA diet. While TNF-α protein was detected in both Nrd1+/+ and Nrd1−/− mouse livers fed the CDAA diet, secretion of TNF-α in Nrd1−/− mice was significantly less than that in Nrd1+/+ mice, indicating the decreased TNF-α shedding in Nrd1−/− mouse liver. Notably, fibrotic changes of the liver, accompanied by the increase of fibrogenic markers, were observed in Nrd1+/+ mice but not in Nrd1−/− mice fed the CDAA diet. Similar to the CDAA diet, fibrotic changes were not observed in Nrd1−/− mice fed a high-fat diet. Thus, deletion of nardilysin prevents the development of diet-induced steatohepatitis and liver fibrogenesis. Nardilysin could be an attractive target for anti-inflammatory therapy against NASH.

Loss of Peripheral Protection in Pancreatic Islets by Proteolysis-Driven Impairment of VTCN1 (B7-H4) Presentation Is Associated with the Development of Autoimmune Diabetes

“…The elevated serum sVTCN1 levels (8) combined with an increased PBMCs' NRD1 expression in RA patients (52), provide an initial insight into this quest, and hint that NRD1-dependent impairment of VTCN1-mediated negative co-stimulation is a general autoimmunity-associated pathway. In agreement, systemic NRD1 deficiency was recently reported to significantly reduce liver inflammation and protect mice from diet-induced nonalcoholic steatohepatitis (53). Our results imply a possibility that stabilization of VTCN1 in liver cells of these mice is a conceivable explanation for such a phenotype.…”

Nardilysin inhibits pancreatitis and suppresses pancreatic ductal adenocarcinoma initiation in mice

“…Moreover, we demonstrated that the production of inflammatory cytokines and the recruitment of inflammatory cells are significantly suppressed concomitant with the suppression of TNFα release on Nrdc deletion in a mouse steatohepatitis model 46. In contrast, in the present study, we showed that Nrdc is expressed in the nucleus of pancreatic acinar cells and that pancreatic Nrdc acts as a tumour suppressor for Kras G12D -driven PanIN and PDA formation most likely through blocking pancreatitis in mice.…”

Nardilysin controls intestinal tumorigenesis through HDAC1/p53–dependent transcriptional regulation

“…When choline-deficient L-amino-acid-defined or high-fat diets are administered, Nrdc -/-mice, unlike the Nrdc +/+ strain, do not develop steatohepatitis (17). NRDC has recently been identified as a dimethyl-H3K4 binding protein (18).…”