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Hepatocyte Nuclear Factor 4α (HNF4α) Plays a Controlling Role in Expression of the Retinoic Acid Receptor β ( RARβ ) Gene in Hepatocytes.

التفاصيل البيبلوغرافية
العنوان: Hepatocyte Nuclear Factor 4α (HNF4α) Plays a Controlling Role in Expression of the Retinoic Acid Receptor β ( RARβ ) Gene in Hepatocytes.
المؤلفون: Zolfaghari R; Department of Nutritional Sciences, Pennsylvania State University, University Park, PA 16802, USA., Bonzo JA; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA., Gonzalez FJ; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA., Ross AC; Department of Nutritional Sciences, Pennsylvania State University, University Park, PA 16802, USA.
المصدر: International journal of molecular sciences [Int J Mol Sci] 2023 May 11; Vol. 24 (10). Date of Electronic Publication: 2023 May 11.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI, [2000-
مواضيع طبية MeSH: Hepatocyte Nuclear Factor 4*/genetics , Hepatocyte Nuclear Factor 4*/metabolism , Hepatocytes*/metabolism , Tretinoin*/pharmacology , Receptors, Retinoic Acid*/genetics, Animals ; Humans ; Mice ; Glucose ; Lipids ; Retinoic Acid Receptor alpha/genetics
مستخلص: HNF4α, a member of the nuclear receptor superfamily, regulates the genes involved in lipid and glucose metabolism. The expression of the RARβ gene in the liver of HNF4α knock-out mice was higher versus wildtype controls, whereas oppositely, RARβ promoter activity was 50% reduced by the overexpression of HNF4α in HepG2 cells, and treatment with retinoic acid (RA), a major metabolite of vitamin A, increased RARβ promoter activity 15-fold. The human RARβ2 promoter contains two DR5 and one DR8 binding motifs, as RA response elements (RARE) proximal to the transcription start site. While DR5 RARE1 was previously reported to be responsive to RARs but not to other nuclear receptors, we show here that mutation in DR5 RARE2 suppresses the promoter response to HNF4α and RARα/RXRα. Mutational analysis of ligand-binding pocket amino acids shown to be critical for fatty acid (FA) binding indicated that RA may interfere with interactions of FA carboxylic acid headgroups with side chains of S190 and R235, and the aliphatic group with I355. These results could explain the partial suppression of HNF4α transcriptional activation toward gene promoters that lack RARE, including APOC3 and CYP2C9, while conversely, HNF4α may bind to RARE sequences in the promoter of the genes such as CYP26A1 and RARβ , activating these genes in the presence of RA. Thus, RA could act as either an antagonist towards HNF4α in genes lacking RAREs, or as an agonist for RARE-containing genes. Overall, RA may interfere with the function of HNF4α and deregulate HNF4α targets genes, including the genes important for lipid and glucose metabolism.
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معلومات مُعتمدة: R01 CA090214 United States CA NCI NIH HHS; CA90214 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: DNA binding site; HNF4α; HNF4α ligand binding domain; RARβ gene promoter; retinoic acid; retinoic acid receptors; retinoic acid response element
المشرفين على المادة: IY9XDZ35W2 (Glucose)
0 (Hepatocyte Nuclear Factor 4)
0 (Lipids)
0 (Retinoic Acid Receptor alpha)
0 (retinoic acid receptor beta)
5688UTC01R (Tretinoin)
0 (Receptors, Retinoic Acid)
تواريخ الأحداث: Date Created: 20230527 Date Completed: 20230531 Latest Revision: 20231223
رمز التحديث: 20231223
مُعرف محوري في PubMed: PMC10218549
DOI: 10.3390/ijms24108608
PMID: 37239961
قاعدة البيانات: MEDLINE
الوصف
تدمد:1422-0067
DOI:10.3390/ijms24108608