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.
|Journal||Cell and Bioscience|
|State||Published - Dec 2022|
Bibliographical noteFunding Information:
Frozen human liver tissues (Healthy and NASH patients, both male and female) were obtained through the Liver Tissue Cell Distribution System (Minneapolis, MN), funded by the National Institutes of Health (Contract# HSN276201200017C).
This study was supported by VA Merit Awards I01BX004033 and 1I01BX003275; Research Career Scientist Award (IK6BX004477); ShEEP grant (1 IS1 BX004777-01); National Institutes of Health Grant R01 DK104893, R01DK-057543, 1R21 AA026629-01; NIH-NCI Cancer Center Support Grant P30 CA 016059.
© 2022, The Author(s).
- Bile acids
- Sphingosine kinase
- Sphingosine-1 phosphate receptor 2
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology (all)