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

Content Provider	Springer Nature : BioMed Central
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
Abstract	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 (HuRhKO) 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 HuRhKO 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.
Related Links	https://cellandbioscience.biomedcentral.com/counter/pdf/10.1186/s13578-022-00910-7.pdf
Ending Page	18
Page Count	18
Starting Page	1
File Format	HTM / HTML
ISSN	20453701
DOI	10.1186/s13578-022-00910-7
Journal	Cell & Bioscience
Issue Number	1
Volume Number	12
Language	English
Publisher	BioMed Central
Publisher Date	2022-10-12
Access Restriction	Open
Subject Keyword	Cell Biology Microbiology Stem Cells Neurobiology Proteomics Bile acids NASH Inflammation Sphingosine kinase Sphingosine-1 phosphate receptor 2
Content Type	Text
Resource Type	Article
Subject	Biochemistry, Genetics and Molecular Biology
Journal Impact Factor	6.1/2023
5-Year Journal Impact Factor	7/2023

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