Curtin Health Innovation Research Institute and Curtin Medical School, Curtin University, Bentley, WA 6102, Australia.
Int J Mol Sci. 2022 Dec 7;23(24):15506. doi: 10.3390/ijms232415506.
In animal studies, HDAC inhibitors such as butyrate have been reported to reduce plasma cholesterol, while conferring protection from diabetes, but studies on the underlying mechanisms are lacking. This study compares the influence of butyrate and other HDAC inhibitors to that of statins on cholesterol metabolism in multiple cell lines, but primarily in HepG2 hepatic cells due to the importance of the liver in cholesterol metabolism. Sodium butyrate reduced HepG2 cholesterol content, as did sodium valproate and the potent HDAC inhibitor trichostatin A, suggesting HDAC inhibition as the exacting mechanism. In contrast to statins, which increase SREBP-2 regulated processes, HDAC inhibition downregulated SREBP-2 targets such as HMGCR and the LDL receptor. Moreover, in contrast to statin treatment, butyrate did not increase cholesterol uptake by HepG2 cells, consistent with its failure to increase LDL receptor expression. Sodium butyrate also reduced ABCA1 and SRB1 protein expression in HepG2 cells, but these effects were not consistent across all cell types. Overall, the underlying mechanism of cell cholesterol lowering by sodium butyrate and HDAC inhibition is consistent with impaired SREBP-2 signalling, and calls into question the possible use of butyrate for lowering of serum LDL cholesterol in humans.
在动物研究中，已有报道称组蛋白去乙酰化酶抑制剂（如丁酸钠）可降低血浆胆固醇，同时预防糖尿病，但缺乏对其潜在机制的研究。本研究比较了丁酸钠和其他组蛋白去乙酰化酶抑制剂与他汀类药物对多种细胞系（主要是 HepG2 肝细胞）胆固醇代谢的影响，因为肝脏在胆固醇代谢中非常重要。丁酸钠降低了 HepG2 细胞的胆固醇含量，丙戊酸钠和强效组蛋白去乙酰化酶抑制剂曲古抑菌素 A 也是如此，这表明组蛋白去乙酰化酶抑制是确切的作用机制。与增加 SREBP-2 调控过程的他汀类药物不同，组蛋白去乙酰化酶抑制下调了 SREBP-2 的靶标，如 HMGCR 和 LDL 受体。此外，与他汀类药物治疗不同，丁酸钠不会增加 HepG2 细胞的胆固醇摄取，这与其不能增加 LDL 受体表达一致。丁酸钠还降低了 HepG2 细胞中的 ABCA1 和 SRB1 蛋白表达，但这些作用在所有细胞类型中并不一致。总的来说，丁酸钠和组蛋白去乙酰化酶抑制降低细胞胆固醇的潜在机制与 SREBP-2 信号受损一致，并质疑丁酸钠在降低人类血清 LDL 胆固醇方面的可能用途。
