التفاصيل البيبلوغرافية
| العنوان: |
Retinoic Acid Receptor β Loss in Hepatocytes Increases Steatosis and Elevates the Integrated Stress Response in Alcohol-Associated Liver Disease. |
| المؤلفون: |
Melis, Marta, Trasino, Steven E., Tang, Xiao-Han, Rappa, Andrew, Zhang, Tuo, Qin, Lihui, Gudas, Lorraine J. |
| المصدر: |
International Journal of Molecular Sciences; Aug2023, Vol. 24 Issue 15, p12035, 15p |
| مصطلحات موضوعية: |
RETINOIC acid receptors, LIVER diseases, OPIOID receptors, LIVER cells, VITAMIN A, FATTY degeneration, FATTY liver, LIPID synthesis |
| مستخلص: |
In alcohol-associated liver disease (ALD), hepatic reductions in vitamin A and perturbations in vitamin A metabolism are common. However, the roles that the vitamin A receptors, termed retinoic acid receptors (RARs), may have in preventing the pathophysiology of ALD remains unclear. Our prior data indicate that a RARβ agonist limits the pathology of alcohol-related liver disease. Thus, we generated liver-specific AlbCre–RARβ knockout (BKO) mice and compared them to wild type (WT) mice in an early ALD model. Both strains showed similar blood ethanol concentrations and ETOH-metabolizing enzymes. However, the livers of pair-fed-BKO and ETOH-BKO mice developed higher levels of steatosis and triglycerides than pair-fed-WT and ETOH-WT mice. The increased hepatic steatosis observed in the pair-fed-BKO and ETOH-BKO mice was associated with higher lipid synthesis/trafficking transcripts and lower beta-oxidation transcripts. ETOH-BKO mice also exhibited a higher integrated stress response (ISR) signature, including higher transcript and protein levels of ATF4 and its target, 4-EBP1. In human hepatocytes (HepG2) that lack RARβ (RARβ-KO), ETOH treatments resulted in greater reactive oxygen species compared to their parental cells. Notably, even without ETOH, ATF4 and 4-EBP1 protein levels were higher in the RARβ-KO cells than in their parental cells. These 4-EBP1 increases were greatly attenuated in cultured ATF4-deficient and RARβ/ATF4-deficient HepG2, suggesting that RARβ is a crucial negative regulator of 4-EBP1 through ATF4 in cultured hepatocytes. Here, we identify RARβ as a negative regulator of lipid metabolism and cellular stress in ALD. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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