Department of Internal Medicine, McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23249, USA.
Cells. 2021 Nov 5;10(11):3027. doi: 10.3390/cells10113027.
Acetaminophen (APAP) overdose is one of the most frequent causes of acute liver failure (ALF). N-acetylcysteine (NAC) is currently being used as part of the standard care in the clinic but its usage has been limited in severe cases, in which liver transplantation becomes the only treatment option. Therefore, there still is a need for a specific and effective therapy for APAP induced ALF. In the current study, we have demonstrated that treatment with 25-Hydroxycholesterol 3-Sulfate (25HC3S) not only significantly reduced mortality but also decreased the plasma levels of liver injury markers, including LDH, AST, and ALT, in APAP overdosed mouse models. 25HC3S also decreased the expression of those genes involved in cell apoptosis, stabilized mitochondrial polarization, and significantly decreased the levels of oxidants, malondialdehyde (MDA), and reactive oxygen species (ROS). Whole genome bisulfite sequencing analysis showed that 25HC3S increased demethylation of CpG in key promoter regions and thereby increased the expression of those genes involved in MAPK-ERK and PI3K-Akt signaling pathways. We concluded that 25HC3S may alleviate APAP induced liver injury via up-regulating the master signaling pathways and maintaining mitochondrial membrane polarization. The results suggest that 25HC3S treatment facilitates the recovery and significantly decreases the mortality of APAP induced acute liver injury and has a synergistic effect with NAC in propylene glycol (PG) for the injury.
对乙酰氨基酚（APAP）过量是急性肝衰竭（ALF）最常见的原因之一。N-乙酰半胱氨酸（NAC）目前被用作临床标准治疗的一部分，但在严重病例中其使用受到限制，在这些病例中，肝移植成为唯一的治疗选择。因此，仍然需要一种针对 APAP 诱导的 ALF 的特异性和有效的治疗方法。在当前的研究中，我们已经证明，用 25-羟基胆固醇 3-硫酸盐（25HC3S）治疗不仅显著降低了死亡率，而且还降低了 APAP 过量的小鼠模型中肝损伤标志物的血浆水平，包括 LDH、AST 和 ALT。25HC3S 还降低了参与细胞凋亡的基因的表达，稳定了线粒体极化，并显著降低了氧化剂、丙二醛（MDA）和活性氧（ROS）的水平。全基因组亚硫酸氢盐测序分析表明，25HC3S 增加了关键启动子区域中 CpG 的去甲基化，从而增加了参与 MAPK-ERK 和 PI3K-Akt 信号通路的基因的表达。我们得出结论，25HC3S 可能通过上调主信号通路并维持线粒体膜极化来减轻 APAP 诱导的肝损伤。结果表明，25HC3S 治疗有助于恢复，显著降低了 APAP 诱导的急性肝损伤的死亡率，并与 NAC 在丙二醇（PG）中的损伤具有协同作用。
