Orphan nuclear receptor ERRγ is a transcriptional regulator of CB1 receptor-mediated TFR2 gene expression in hepatocytes

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Title
Orphan nuclear receptor ERRγ is a transcriptional regulator of CB1 receptor-mediated TFR2 gene expression in hepatocytes
Author(s)
B E Kim; B Choi; W R Park; Y J Kim; I Y Kim; Y S Jung; Yong-Hoon KimChul-Ho Lee; H S Choi; D K Kim
Bibliographic Citation
International Journal of Molecular Sciences, vol. 22, no. 11, pp. 6021-6021
Publication Year
2021
Abstract
Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is an important transcription factor modulating gene transcription involved in endocrine control of liver metabolism. Transferrin receptor 2 (TFR2), a carrier protein for transferrin, is involved in hepatic iron overload in alcoholic liver disease (ALD). However, TFR2 gene transcriptional regulation in hepatocytes remains largely unknown. In this study, we described a detailed molecular mechanism of hepatic TFR2 gene expression involving ERRγ in response to an endocannabinoid 2-arachidonoylglycerol (2-AG). Treatment with 2-AG and arachidonyl-2′-chloroethylamide, a selective cannabinoid receptor type 1 (CB1) receptor agonist, increased ERRγ and TFR2 expression in hepatocytes. Overexpression of ERRγ was sufficient to induce TFR2 expression in both human and mouse hepatocytes. In addition, ERRγ knockdown significantly decreased 2-AG or alcohol-mediated TFR2 gene expression in cultured hepatocytes and mouse livers. Finally, deletion and mutation analysis of the TFR2 gene promoter demonstrated that ERRγ directly modulated TFR2 gene transcription via binding to an ERR-response element. This was further confirmed by chromatin immunoprecipitation assay. Taken together, these results reveal a previously unrecognized role of ERRγ in the transcriptional regulation of TFR2 gene expression in response to alcohol.
Keyword
Estrogen-related receptor γ (ERRγ)Transferrin receptor 2 (TFR2)Cannabinoid receptor type 1 (CB1)Orphan nuclear receptorgene regulation2-AGHepatic iron overloadAlcoholic liver disease
ISSN
1661-6596
Publisher
MDPI
DOI
http://dx.doi.org/10.3390/ijms22116021
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
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