Hepatic leukocyte immunoglobulin‐like receptor B4 (LILRB4) attenuates nonalcoholic fatty liver disease via SHP1‐TRAF6 pathway

Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent liver pathology marked by hepatic steatosis and commonly accompanied by systematic inflammation and metabolic disorder. Despite an accumulating number of studies, no pharmacological strategy is available to treat this condition in the clinic. The current work applied extensive gain- and loss-of-function approaches to identify the key immune factor leukocyte immunoglobulin-like receptor B4 (LILRB4) as a negative regulator of NAFLD. The hepatocyte-specific knockout of LILRB4 (LILRB4-HKO) significantly exacerbated high-fat diet (HFD)-induced insulin resistance, glucose metabolic imbalance, hepatic lipid accumulation, and systematic inflammation in mice, whereas LILRB4 overexpression in hepatocytes showed a completely opposite phenotype relative to that of LILRB4-HKO mice when compared to their corresponding controls. Further investigations on molecular mechanism demonstrated that LILRB4 recruit SHP1 for inhibiting TRAF6 ubiquitination and subsequently inactivating NF-κB and MAPK cascades. From a therapeutic perspective, the overexpression of LILRB4 in a genetic model of NAFLD, ob/ob mice, largely reversed the inherent hepatic steatosis, inflammation, and metabolic disorder. Conclusions: Targeting hepatic LILRB4 to improve its expression or activation might represent a promising strategy for the treatment of NAFLD as well as related liver and metabolic diseases. This article is protected by copyright. All rights reserved.