25-Hydroxycholesterol 3-Sulfate Recovers Acetaminophen Induced Acute Liver Injury via Stabilizing Mitochondria in Mouse Models

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. T...

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Autores principales:	Yaping Wang, William M. Pandak, Edward J. Lesnefsky, Phillip B. Hylemon, Shunlin Ren
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	25HC3S oxysterol sulfation acute liver injury acetaminophen DNA CpG methylation Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/802b4b37a03c4fd1b8cfd472f7144640
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spelling	oai:doaj.org-article:802b4b37a03c4fd1b8cfd472f71446402021-11-25T17:10:36Z25-Hydroxycholesterol 3-Sulfate Recovers Acetaminophen Induced Acute Liver Injury via Stabilizing Mitochondria in Mouse Models10.3390/cells101130272073-4409https://doaj.org/article/802b4b37a03c4fd1b8cfd472f71446402021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3027https://doaj.org/toc/2073-4409Acetaminophen (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 <sup>5m</sup>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.Yaping WangWilliam M. PandakEdward J. LesnefskyPhillip B. HylemonShunlin RenMDPI AGarticle25HC3Soxysterol sulfationacute liver injuryacetaminophenDNA CpG methylationBiology (General)QH301-705.5ENCells, Vol 10, Iss 3027, p 3027 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	25HC3S oxysterol sulfation acute liver injury acetaminophen DNA CpG methylation Biology (General) QH301-705.5
spellingShingle	25HC3S oxysterol sulfation acute liver injury acetaminophen DNA CpG methylation Biology (General) QH301-705.5 Yaping Wang William M. Pandak Edward J. Lesnefsky Phillip B. Hylemon Shunlin Ren 25-Hydroxycholesterol 3-Sulfate Recovers Acetaminophen Induced Acute Liver Injury via Stabilizing Mitochondria in Mouse Models
description	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 <sup>5m</sup>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.
format	article
author	Yaping Wang William M. Pandak Edward J. Lesnefsky Phillip B. Hylemon Shunlin Ren
author_facet	Yaping Wang William M. Pandak Edward J. Lesnefsky Phillip B. Hylemon Shunlin Ren
author_sort	Yaping Wang
title	25-Hydroxycholesterol 3-Sulfate Recovers Acetaminophen Induced Acute Liver Injury via Stabilizing Mitochondria in Mouse Models
title_short	25-Hydroxycholesterol 3-Sulfate Recovers Acetaminophen Induced Acute Liver Injury via Stabilizing Mitochondria in Mouse Models
title_full	25-Hydroxycholesterol 3-Sulfate Recovers Acetaminophen Induced Acute Liver Injury via Stabilizing Mitochondria in Mouse Models
title_fullStr	25-Hydroxycholesterol 3-Sulfate Recovers Acetaminophen Induced Acute Liver Injury via Stabilizing Mitochondria in Mouse Models
title_full_unstemmed	25-Hydroxycholesterol 3-Sulfate Recovers Acetaminophen Induced Acute Liver Injury via Stabilizing Mitochondria in Mouse Models
title_sort	25-hydroxycholesterol 3-sulfate recovers acetaminophen induced acute liver injury via stabilizing mitochondria in mouse models
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/802b4b37a03c4fd1b8cfd472f7144640
work_keys_str_mv	AT yapingwang 25hydroxycholesterol3sulfaterecoversacetaminopheninducedacuteliverinjuryviastabilizingmitochondriainmousemodels AT williammpandak 25hydroxycholesterol3sulfaterecoversacetaminopheninducedacuteliverinjuryviastabilizingmitochondriainmousemodels AT edwardjlesnefsky 25hydroxycholesterol3sulfaterecoversacetaminopheninducedacuteliverinjuryviastabilizingmitochondriainmousemodels AT phillipbhylemon 25hydroxycholesterol3sulfaterecoversacetaminopheninducedacuteliverinjuryviastabilizingmitochondriainmousemodels AT shunlinren 25hydroxycholesterol3sulfaterecoversacetaminopheninducedacuteliverinjuryviastabilizingmitochondriainmousemodels
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25-Hydroxycholesterol 3-Sulfate Recovers Acetaminophen Induced Acute Liver Injury via Stabilizing Mitochondria in Mouse Models

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