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| Status |
Public on Nov 28, 2023 |
| Title |
Retinoic Acid Receptor β Loss in Hepatocytes Increases Steatosis and Elevates the Integrated Stress Response in Alcohol-Associated Liver Disease |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Background & Aims: Alcohol-associated liver disease (ALD) is associated with loss of vitamin A (retinoids), increased steatosis, and greater oxidative stress. Although a strong correlation has been observed between loss of retinoids and ALD, if retinoid loss plays a causal role in the pathophysiology of ALD is not clear. Approach & Results: Based on our prior published data indicating that a selective retinoic acid receptor beta (RARβ) agonist limits nonalcohol-related liver disease (NAFLD) pathology, we generated AlbCre;RARβ knockout (BKO) mice and fed these mice a Lieber DeCarli ethanol diet (ETOH). We also generated cultured human hepatocytes (HepG2) that lack RARβ (RARβ-KO) and treated them with ETOH. Here we show that the livers of BKO mice develop greater steatosis, oxidative stress (assessed by 4-HNE), cell proliferation, and hypertrophy on the ETOH diet when compared to wild type (WT). Compared to ETOH-WT mice, the ETOH-BKO mice also exhibit higher hepatic transcript levels of ATF4, MYC, a subset of integrated stress response (ISR) genes (Trib3, Asns, Nqo1, and Hmox1), and the common ATF4 and MYC target, 4EBP1(EIF4EBP1). In RARβ-KO HepG2 cells, ETOH treatments (24 and 72h) resulted in more rapid and greater development of reactive oxygen species compared to parental HepG2. Notably, even without ETOH, ATF4 protein was higher in the RARβ-KO than in parental HepG2. Conclusions: Our research identifies hepatocyte RARβ as a crucial negative regulator of oxidative stress, MYC, ATF4, and proliferation in ALD.
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| Overall design |
Comparative gene expression profiling analysis of RNA-seq data for mouse liver tissue of females C57Bl/6 mice treated with an ethanol-based diet and a matched control diet.
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| Contributor(s) |
Melis M, Trasino SE, Tang X, Rappa A, Zhang T, Qin L, Gudas LJ |
| Citation(s) |
37569418 |
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| Submission date |
Dec 24, 2022 |
| Last update date |
Nov 28, 2023 |
| Contact name |
Lorraine J Gudas |
| E-mail(s) |
ljgudas@med.cornell.edu
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| Phone |
(212) 746-6254
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| Organization name |
Weill Cornell Medicine
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| Department |
Pharmacology
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| Street address |
1300 York Ave E405
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10065 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA915600 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE221713_RNA_Seq.xls.gz |
1.6 Mb |
(ftp)(http) |
XLS |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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