Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
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
_version_ 1783314471669727232
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
work_keys_str_mv AT luyao hepaticleukocyteimmunoglobulinlikereceptorb4lilrb4attenuatesnonalcoholicfattyliverdiseaseviashp1traf6pathway
AT jiangzhou hepaticleukocyteimmunoglobulinlikereceptorb4lilrb4attenuatesnonalcoholicfattyliverdiseaseviashp1traf6pathway
AT daihaijiang hepaticleukocyteimmunoglobulinlikereceptorb4lilrb4attenuatesnonalcoholicfattyliverdiseaseviashp1traf6pathway
AT miaorujia hepaticleukocyteimmunoglobulinlikereceptorb4lilrb4attenuatesnonalcoholicfattyliverdiseaseviashp1traf6pathway
AT shujingxian hepaticleukocyteimmunoglobulinlikereceptorb4lilrb4attenuatesnonalcoholicfattyliverdiseaseviashp1traf6pathway
AT guhaotian hepaticleukocyteimmunoglobulinlikereceptorb4lilrb4attenuatesnonalcoholicfattyliverdiseaseviashp1traf6pathway
AT liuxing hepaticleukocyteimmunoglobulinlikereceptorb4lilrb4attenuatesnonalcoholicfattyliverdiseaseviashp1traf6pathway
AT huangzhijun hepaticleukocyteimmunoglobulinlikereceptorb4lilrb4attenuatesnonalcoholicfattyliverdiseaseviashp1traf6pathway
AT yangguoping hepaticleukocyteimmunoglobulinlikereceptorb4lilrb4attenuatesnonalcoholicfattyliverdiseaseviashp1traf6pathway
AT chenalexf hepaticleukocyteimmunoglobulinlikereceptorb4lilrb4attenuatesnonalcoholicfattyliverdiseaseviashp1traf6pathway
AT yuanhong hepaticleukocyteimmunoglobulinlikereceptorb4lilrb4attenuatesnonalcoholicfattyliverdiseaseviashp1traf6pathway
AT liying hepaticleukocyteimmunoglobulinlikereceptorb4lilrb4attenuatesnonalcoholicfattyliverdiseaseviashp1traf6pathway
AT caijingjing hepaticleukocyteimmunoglobulinlikereceptorb4lilrb4attenuatesnonalcoholicfattyliverdiseaseviashp1traf6pathway