Abstract
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 5mCpG 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.
Highlights
The results showed that 25-Hydroxycholesterol 3-Sulfate (25HC3S) significantly decreased mortality, improved hepatic function, increased mitochondrial polarization, and reduced the levels of oxidants and cell death following APAP overdose
350 mg and 600 mg/kg of APAP, were used: (1) To study the effect of 25HC3S on liver injury induced by APAP overdose, 12-week-old male C57BL/6J mice (Jackson Laboratory, Bar Harbor, ME, USA) were weight-pair assigned into three groups, control, vehicle, and 25HC3S groups
In order to determine the effect of 25HC3S on liver injury in APAP challenged mice, 12week-old male C57BL/6J mice were weight-pair assigned into three groups, the control, the vehicle, and the 25HC3S
Summary
Acute liver failure (ALF) involves the rapid loss of liver function [1]. The clinical presentation of ALF usually includes liver dysfunction, coagulopathy, development of encephalopathy, multi organ failure, and death in over 50% of the cases [2]. Patients with ALF develop hepatic inflammation leading to fulminant hepatic necrosis and apoptosis. Causes of ALF include, but are not limited to, drug toxicity, viruses, toxins, and ischemia [3]. In the United States and Western Europe, over 50% of all cases of ALF have been attributed to drug-induced hepatotoxicity, especially, acetaminophen (APAP, known as paracetamol) overdose-induced ALF, which exceeds other drugs by a 4:1 ratio. There is an unmet medical need to develop an effective therapy for ALF
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