Hepatocyte Nuclear Factor 4α (HNF4α) Plays a Controlling Role in Expression of the Retinoic Acid Receptor β (RARβ) Gene in Hepatocytes.
Hepatocyte Nuclear Factor 4α (HNF4α) Plays a Controlling Role in Expression of the Retinoic Acid Receptor β (RARβ) Gene in Hepatocytes.
复制标题
肝细胞核因子4α（HNF4α）在视黄酸受体β（RARβ）基因在肝细胞中的表达中起着控制作用。
DOI：
10.3390/ijms24108608
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发表时间：
2023-05-11
影响因子：
5.6
通讯作者：
Ross, A. Catharine
中科院分区：
文献类型：
--
作者：
Zolfaghari, Reza;Bonzo, Jessica A.;Gonzalez, Frank J.;Ross, A. Catharine
关键词：
HNF4 α是核受体超家族的成员，调节参与脂质和葡萄糖代谢的基因。与野生型对照相比，HNF4 α基因敲除小鼠肝脏中RAR β基因的表达更高，而相反，在HepG2细胞中过表达HNF4 α使RAR β启动子活性降低50%，并且用维生素A的主要代谢物视黄酸（RA）处理使RAR β启动子活性增加15倍。人RAR β 2启动子含有两个DR5和一个DR8结合基序，作为转录起始位点附近的RA应答元件（RARE）。虽然先前报道DR5 RARE 1对RAR有反应，但对其他核受体没有反应，但我们在这里发现DR5 RARE 2的突变抑制了启动子对HNF 4 α和RAR α/RXR α的反应。对脂肪酸（FA）结合关键的配体结合口袋氨基酸的突变分析表明，RA可能会干扰FA羧酸头基与S190和R235侧链的相互作用，以及脂肪族基团与I355的相互作用。这些结果可以解释HNF 4 α对缺乏RARE的基因启动子（包括APOC 3和CYP 2C 9）的转录激活的部分抑制，而相反，HNF 4 α可能与CYP 26 A1和RAR β等基因启动子中的RARE序列结合，在RA存在的情况下激活这些基因。因此，RA可以作为HNF 4 α的拮抗剂在缺乏RARE的基因中发挥作用，也可以作为含RARE基因的激动剂发挥作用。总之，RA可能干扰HNF 4 α的功能，并使HNF 4 α靶向基因（包括对脂质和葡萄糖代谢重要的基因）失调。
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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影响因子：
10.5
作者：
Abu-Abed, S;Dollé, P;Petkovich, M
通讯作者：
Petkovich, M
影响因子：
4.8
作者：
Dhe-Paganon, S;Duda, K;Shoelson, SE
通讯作者：
Shoelson, SE
影响因子：
5.3
作者：
Hayhurst, GP;Lee, YH;Gonzalez, FJ
通讯作者：
Gonzalez, FJ
DOI：
10.1016/j.jnutbio.2021.108814
发表时间：
2021-12
期刊：
The Journal of nutritional biochemistry
影响因子：
--
作者：
Chai Z;Lyu Y;Chen Q;Wei CH;Snyder LM;Weaver V;Sebastian A;Albert I;Li Q;Cantorna MT;Ross AC
通讯作者：
Ross AC
影响因子：
13.5
作者：
Jover, R;Bort, R;Castell, JV
通讯作者：
Castell, JV