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RNA binding protein HuR protects against NAFLD by suppressing long noncoding RNA H19 expression

BACKGROUND: NAFLD has become the most common chronic liver disease worldwide. Human antigen R (HuR), an RNA-binding protein, is an important post-transcriptional regulator. HuR has been reported as a key player in regulating lipid homeostasis in the liver and adipose tissues by using tissue-specific...

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Autores principales: Wang, Yanyan, Tai, Yun-Ling, Way, Grayson, Zeng, Jing, Zhao, Derrick, Su, Lianyong, Jiang, Xixian, Jackson, Kaitlyn G., Wang, Xuan, Gurley, Emily C., Liu, Jinze, Liu, Jinpeng, Chen, Weidong, Wang, Xiang-Yang, Sanyal, Arun J., Hylemon, Phillip B., Zhou, Huiping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9558407/
https://www.ncbi.nlm.nih.gov/pubmed/36224648
http://dx.doi.org/10.1186/s13578-022-00910-7
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author Wang, Yanyan
Tai, Yun-Ling
Way, Grayson
Zeng, Jing
Zhao, Derrick
Su, Lianyong
Jiang, Xixian
Jackson, Kaitlyn G.
Wang, Xuan
Gurley, Emily C.
Liu, Jinze
Liu, Jinpeng
Chen, Weidong
Wang, Xiang-Yang
Sanyal, Arun J.
Hylemon, Phillip B.
Zhou, Huiping
author_facet Wang, Yanyan
Tai, Yun-Ling
Way, Grayson
Zeng, Jing
Zhao, Derrick
Su, Lianyong
Jiang, Xixian
Jackson, Kaitlyn G.
Wang, Xuan
Gurley, Emily C.
Liu, Jinze
Liu, Jinpeng
Chen, Weidong
Wang, Xiang-Yang
Sanyal, Arun J.
Hylemon, Phillip B.
Zhou, Huiping
author_sort Wang, Yanyan
collection PubMed
description BACKGROUND: NAFLD has become the most common chronic liver disease worldwide. Human antigen R (HuR), an RNA-binding protein, is an important post-transcriptional regulator. HuR has been reported as a key player in regulating lipid homeostasis in the liver and adipose tissues by using tissue-specific HuR knockout mice. However, the underlying mechanism by which hepatocyte-specific HuR regulates hepatic lipid metabolism under metabolic stress remains unclear and is the focus of this study. METHODS: Hepatocyte-specific HuR deficient mice (HuR(hKO)) and age-/gender-matched control mice, as well as long-noncoding RNA H19 knockout mice (H19(−/−)), were fed a Western Diet plus sugar water (WDSW). Hepatic lipid accumulation, inflammation and fibrosis were examined by histology, RNA transcriptome analysis, qRT–PCR, and Western blot analysis. Bile acid composition was measured using LC–MS/MS. RESULTS: Hepatocyte-specific deletion of HuR not only significantly increased hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also markedly induced inflammation by increasing immune cell infiltration and neutrophil activation under metabolic stress. In addition, hepatic deficiency of HuR disrupted bile acid homeostasis and enhanced liver fibrosis. Mechanistically, HuR is a repressor of H19 expression. Analysis of a recently published dataset (GSE143358) identified H19 as the top-upregulated gene in liver-specific HuR knockout mice. Similarly, hepatocyte-specific deficiency of HuR dramatically induced the expression of H19 and sphingosine-1 phosphate receptor 2 (S1PR2), but reduced the expression of sphingosine kinase 2 (SphK2). WDSW-induced hepatic lipid accumulation was alleviated in H19(−/−) mice. Furthermore, the downregulation of H19 alleviated WDSW-induced NAFLD in HuR(hKO) mice. CONCLUSIONS: HuR not only functions as an RNA binding protein to modulate post-transcriptional gene expression but also regulates H19 promoter activity. Hepatic HuR is an important regulator of hepatic lipid metabolism via modulating H19 expression. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-022-00910-7.
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spelling pubmed-95584072022-10-14 RNA binding protein HuR protects against NAFLD by suppressing long noncoding RNA H19 expression Wang, Yanyan Tai, Yun-Ling Way, Grayson Zeng, Jing Zhao, Derrick Su, Lianyong Jiang, Xixian Jackson, Kaitlyn G. Wang, Xuan Gurley, Emily C. Liu, Jinze Liu, Jinpeng Chen, Weidong Wang, Xiang-Yang Sanyal, Arun J. Hylemon, Phillip B. Zhou, Huiping Cell Biosci Research BACKGROUND: NAFLD has become the most common chronic liver disease worldwide. Human antigen R (HuR), an RNA-binding protein, is an important post-transcriptional regulator. HuR has been reported as a key player in regulating lipid homeostasis in the liver and adipose tissues by using tissue-specific HuR knockout mice. However, the underlying mechanism by which hepatocyte-specific HuR regulates hepatic lipid metabolism under metabolic stress remains unclear and is the focus of this study. METHODS: Hepatocyte-specific HuR deficient mice (HuR(hKO)) and age-/gender-matched control mice, as well as long-noncoding RNA H19 knockout mice (H19(−/−)), were fed a Western Diet plus sugar water (WDSW). Hepatic lipid accumulation, inflammation and fibrosis were examined by histology, RNA transcriptome analysis, qRT–PCR, and Western blot analysis. Bile acid composition was measured using LC–MS/MS. RESULTS: Hepatocyte-specific deletion of HuR not only significantly increased hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also markedly induced inflammation by increasing immune cell infiltration and neutrophil activation under metabolic stress. In addition, hepatic deficiency of HuR disrupted bile acid homeostasis and enhanced liver fibrosis. Mechanistically, HuR is a repressor of H19 expression. Analysis of a recently published dataset (GSE143358) identified H19 as the top-upregulated gene in liver-specific HuR knockout mice. Similarly, hepatocyte-specific deficiency of HuR dramatically induced the expression of H19 and sphingosine-1 phosphate receptor 2 (S1PR2), but reduced the expression of sphingosine kinase 2 (SphK2). WDSW-induced hepatic lipid accumulation was alleviated in H19(−/−) mice. Furthermore, the downregulation of H19 alleviated WDSW-induced NAFLD in HuR(hKO) mice. CONCLUSIONS: HuR not only functions as an RNA binding protein to modulate post-transcriptional gene expression but also regulates H19 promoter activity. Hepatic HuR is an important regulator of hepatic lipid metabolism via modulating H19 expression. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-022-00910-7. BioMed Central 2022-10-12 /pmc/articles/PMC9558407/ /pubmed/36224648 http://dx.doi.org/10.1186/s13578-022-00910-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Wang, Yanyan
Tai, Yun-Ling
Way, Grayson
Zeng, Jing
Zhao, Derrick
Su, Lianyong
Jiang, Xixian
Jackson, Kaitlyn G.
Wang, Xuan
Gurley, Emily C.
Liu, Jinze
Liu, Jinpeng
Chen, Weidong
Wang, Xiang-Yang
Sanyal, Arun J.
Hylemon, Phillip B.
Zhou, Huiping
RNA binding protein HuR protects against NAFLD by suppressing long noncoding RNA H19 expression
title RNA binding protein HuR protects against NAFLD by suppressing long noncoding RNA H19 expression
title_full RNA binding protein HuR protects against NAFLD by suppressing long noncoding RNA H19 expression
title_fullStr RNA binding protein HuR protects against NAFLD by suppressing long noncoding RNA H19 expression
title_full_unstemmed RNA binding protein HuR protects against NAFLD by suppressing long noncoding RNA H19 expression
title_short RNA binding protein HuR protects against NAFLD by suppressing long noncoding RNA H19 expression
title_sort rna binding protein hur protects against nafld by suppressing long noncoding rna h19 expression
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9558407/
https://www.ncbi.nlm.nih.gov/pubmed/36224648
http://dx.doi.org/10.1186/s13578-022-00910-7
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