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

Hepatology. 2018 Apr;67(4):1303-1319. doi: 10.1002/hep.29633. Epub 2018 Feb 7.


Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent liver pathology characterized 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. In this study, we 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) exacerbated high-fat diet-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 with their corresponding controls. Further investigations of molecular mechanisms demonstrated that LILRB4 recruits SHP1 to inhibit TRAF6 ubiquitination and subsequent inactivation of nuclear factor kappa B and mitogen-activated protein kinase 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.

Conclusion: Targeting hepatic LILRB4 to improve its expression or activation represents a promising strategy for the treatment of NAFLD as well as related liver and metabolic diseases. (Hepatology 2018;67:1303-1319).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Culture Techniques
  • Fluorescent Antibody Technique
  • Gene Expression Regulation
  • Glucose Tolerance Test / methods
  • Hepatocytes / metabolism*
  • Hepatocytes / pathology
  • Humans
  • Insulin Resistance
  • Liver / pathology
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Receptors, Immunologic / metabolism*
  • Signal Transduction
  • TNF Receptor-Associated Factor 6 / metabolism*


  • Lilrb4 protein, mouse
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • TNF Receptor-Associated Factor 6
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Ptpn6 protein, mouse