Abstract
Abstract Alcoholic liver disease (ALD) characterized by hepatic steatosis, fibrosis, and inflammation is a global health problem caused by chronic consumption of alcohol. NOD-like receptor family member NLRP12 has emerged as a negative regulator of inflammation in diverse pathophysiological conditions. We previously showed that Nlrp12 deficiency promotes hepatocellular carcinoma (HCC) in mice and increased HCC was associated with higher hepatic steatosis and inflammation. However, the role of NLRP12 in alcohol-induced liver disorder was unknown. Here we investigated the role of NLRP12 in ALD using mouse models and in vitro studies. WT and Nlrp12-/- mice were fed with an alcohol diet for 4 weeks. Histopathological analysis showed increased steatosis in Nlrp12-/- mouse livers. Consistently, there was higher expression of proinflammatory cytokines and chemokines, and activation of JNK and AKT pathways as measured by real-time PCR and Western blotting, respectively. To understand the role of NLRP12 in alcohol-induced steatosis and inflammation, we stimulated primary hepatocytes from wild-type and Nlrp12-/- mice with ethanol. Interestingly, inflammatory responses as well as activation of JNK and AKT were higher in alcohol-treated Nlrp12-/- hepatocytes compared to those of wild-type. Similar responses were also seen in Nlrp12-/- macrophages stimulated with alcohol. Together these data suggest that NLRP12 is a critical negative regulator of alcohol induced liver disorders.
Published Version
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