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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 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 condi...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900726/ https://www.ncbi.nlm.nih.gov/pubmed/29091299 http://dx.doi.org/10.1002/hep.29633 |
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author | Lu, Yao Jiang, Zhou Dai, Haijiang Miao, Rujia Shu, Jingxian Gu, Haotian Liu, Xing Huang, Zhijun Yang, Guoping Chen, Alex F. Yuan, Hong Li, Ying Cai, Jingjing |
author_facet | Lu, Yao Jiang, Zhou Dai, Haijiang Miao, Rujia Shu, Jingxian Gu, Haotian Liu, Xing Huang, Zhijun Yang, Guoping Chen, Alex F. Yuan, Hong Li, Ying Cai, Jingjing |
author_sort | Lu, Yao |
collection | PubMed |
description | 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) |
format | Online Article Text |
id | pubmed-5900726 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-59007262018-04-23 Hepatic leukocyte immunoglobulin‐like receptor B4 (LILRB4) attenuates nonalcoholic fatty liver disease via SHP1‐TRAF6 pathway Lu, Yao Jiang, Zhou Dai, Haijiang Miao, Rujia Shu, Jingxian Gu, Haotian Liu, Xing Huang, Zhijun Yang, Guoping Chen, Alex F. Yuan, Hong Li, Ying Cai, Jingjing Hepatology Original Articles 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) John Wiley and Sons Inc. 2018-02-07 2018-04 /pmc/articles/PMC5900726/ /pubmed/29091299 http://dx.doi.org/10.1002/hep.29633 Text en © 2017 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Articles Lu, Yao Jiang, Zhou Dai, Haijiang Miao, Rujia Shu, Jingxian Gu, Haotian Liu, Xing Huang, Zhijun Yang, Guoping Chen, Alex F. Yuan, Hong Li, Ying Cai, Jingjing Hepatic leukocyte immunoglobulin‐like receptor B4 (LILRB4) attenuates nonalcoholic fatty liver disease via SHP1‐TRAF6 pathway |
title | Hepatic leukocyte immunoglobulin‐like receptor B4 (LILRB4) attenuates nonalcoholic fatty liver disease via SHP1‐TRAF6 pathway |
title_full | Hepatic leukocyte immunoglobulin‐like receptor B4 (LILRB4) attenuates nonalcoholic fatty liver disease via SHP1‐TRAF6 pathway |
title_fullStr | Hepatic leukocyte immunoglobulin‐like receptor B4 (LILRB4) attenuates nonalcoholic fatty liver disease via SHP1‐TRAF6 pathway |
title_full_unstemmed | Hepatic leukocyte immunoglobulin‐like receptor B4 (LILRB4) attenuates nonalcoholic fatty liver disease via SHP1‐TRAF6 pathway |
title_short | Hepatic leukocyte immunoglobulin‐like receptor B4 (LILRB4) attenuates nonalcoholic fatty liver disease via SHP1‐TRAF6 pathway |
title_sort | hepatic leukocyte immunoglobulin‐like receptor b4 (lilrb4) attenuates nonalcoholic fatty liver disease via shp1‐traf6 pathway |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900726/ https://www.ncbi.nlm.nih.gov/pubmed/29091299 http://dx.doi.org/10.1002/hep.29633 |
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