Brahma Related Gene 1 (Brg1) Regulates Cellular Cholesterol Synthesis by Acting as a Co-factor for SREBP2
Brahma Related Gene 1 (Brg1) Regulates Cellular Cholesterol Synthesis by Acting as a Co-factor for SREBP2
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Brahma 相关基因 1 (Brg1) 通过作为 SREBP2 的辅助因子来调节细胞胆固醇合成
DOI：
10.3389/fcell.2020.00259
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发表时间：
2020-05-15
影响因子：
5.5
通讯作者：
Xu, Yong
中科院分区：
文献类型：
--
作者：
Fan, Zhiwen;Kong, Ming;Xu, Yong
肝细胞是胆固醇代谢的枢纽。肝脏中胆固醇合成增加与高胆固醇血症相关，并导致许多心血管和代谢疾病的发病机制。固醇反应元件结合蛋白2（SREBP 2）通过激活胆固醇生物合成途径中限速酶的转录来调节肝脏胆固醇代谢。潜在的表观遗传机制还没有很好地理解。我们在这里报告，Brg1（一种染色质重塑蛋白）肝细胞特异性敲除（CKO）的小鼠，与野生型（WT）同窝小鼠相比，在接受高事实饮食（HFD）或蛋氨酸和胆碱缺乏饮食（MCD）时，肝脏胆固醇水平降低。由于BRG 1缺乏导致的胆固醇水平下调伴随着胆固醇基因转录的减弱。同样，BRG 1敲低肝细胞显着抑制诱导胆固醇基因的脂质耗竭公式。Brg1与SREBP2相互作用，并被SREBP2募集到胆固醇基因启动子。相反，Brg1缺陷抑制了SREBP 2在靶启动子上的发生，可能是通过调节胆固醇基因启动子上的H3K9甲基化。从机制上讲，Brg1招募H3K9甲基转移酶KDM3A来共同调节促胆固醇生成的转录。KDM3A沉默抑制肝细胞中的胆固醇生成反应，相当于Brg1缺乏。总之，我们的数据证明了一种新的表观遗传途径，有助于肝细胞中SREBP 2依赖性胆固醇合成。
Hepatocyte is a hub for cholesterol metabolism. Augmented synthesis of cholesterol in the liver is associated with hypercholesterolemia and contributes to the pathogenesis of a host of cardiovascular and metabolic diseases. Sterol response element binding protein 2 (SREBP2) regulates hepatic cholesterol metabolism by activating the transcription of rate-limiting enzymes in the cholesterol biosynthesis pathway. The underlying epigenetic mechanism is not well understood. We report here that mice with hepatocyte-specific knockout (CKO) of Brg1, a chromatin remodeling protein, exhibit reduced levels of hepatic cholesterol compared to the wild type (WT) littermates when placed on a high-fact diet (HFD) or a methionine-and-choline-deficient diet (MCD). Down-regulation of cholesterol levels as a result of BRG1 deficiency was accompanied by attenuation of cholesterogenic gene transcription. Likewise, BRG1 knockdown in hepatocytes markedly suppressed the induction of cholesterogenic genes by lipid depletion formulas. Brg1 interacted with SREBP2 and was recruited by SREBP2 to the cholesterogenic gene promoters. Reciprocally, Brg1 deficiency dampened the occupancies of SREBP2 on target promoters likely through modulating H3K9 methylation on the cholesterogenic gene promoters. Mechanistically, Brg1 recruited the H3K9 methyltransferase KDM3A to co-regulate pro-cholesterogenic transcription. KDM3A silencing dampened the cholesterogenic response in hepatocytes equivalent to Brg1 deficiency. In conclusion, our data demonstrate a novel epigenetic pathway that contributes to SREBP2-dependent cholesterol synthesis in hepatocytes.