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Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity

Oxysterol-binding protein like 2 (OSBPL2) was identified as a novel causal gene for autosomal dominant nonsyndromic hearing loss. However, the pathogenesis of OSBPL2 deficits in ADNSHL was still unclear. The function of OSBPL2 as a lipid-sensing regulator in multiple cellular processes suggested tha...

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Autores principales: Wang, Hongshun, Lin, Changsong, Yao, Jun, Shi, Hairong, Zhang, Cui, Wei, Qinjun, Lu, Yajie, Chen, Zhibin, Xing, Guangqian, Cao, Xin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700064/
https://www.ncbi.nlm.nih.gov/pubmed/31427568
http://dx.doi.org/10.1038/s41419-019-1858-9
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author Wang, Hongshun
Lin, Changsong
Yao, Jun
Shi, Hairong
Zhang, Cui
Wei, Qinjun
Lu, Yajie
Chen, Zhibin
Xing, Guangqian
Cao, Xin
author_facet Wang, Hongshun
Lin, Changsong
Yao, Jun
Shi, Hairong
Zhang, Cui
Wei, Qinjun
Lu, Yajie
Chen, Zhibin
Xing, Guangqian
Cao, Xin
author_sort Wang, Hongshun
collection PubMed
description Oxysterol-binding protein like 2 (OSBPL2) was identified as a novel causal gene for autosomal dominant nonsyndromic hearing loss. However, the pathogenesis of OSBPL2 deficits in ADNSHL was still unclear. The function of OSBPL2 as a lipid-sensing regulator in multiple cellular processes suggested that OSBPL2 might play an important role in the regulation of cholesterol-homeostasis, which was essential for inner ear. In this study the potential roles of OSBPL2 in cholesterol biosynthesis and ROS production were investigated in Osbpl2-KO OC1 cells and osbpl2b-KO zebrafish. RNA-seq-based analysis suggested that OSBPL2 was implicated in cholesterol biosynthesis and AMPK signaling pathway. Furthermore, Osbpl2/osbpl2b-KO resulted in a reduction of AMPK activity and up-regulation of Srebp2/srebp2, Hmgcr/hmgcr and Hmgcs1/hmgcs1, key genes in the sterol biosynthetic pathway and associated with AMPK signaling. In addition, OSBPL2 was also found to interact with ATIC, key activator of AMPK. The levels of total cholesterol and ROS in OC1 cells or zebrafish inner ear were both increased in Osbpl2/osbpl2b-KO mutants and the mitochondrial damage was detected in Osbpl2-KO OC1 cells. This study uncovered the regulatory roles of OSBPL2 in cellular cholesterol biosynthesis and ROS production. These founds might contribute to the deep understanding of the pathogenesis of OSBPL2 mutation in ADNSHL.
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spelling pubmed-67000642019-08-20 Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity Wang, Hongshun Lin, Changsong Yao, Jun Shi, Hairong Zhang, Cui Wei, Qinjun Lu, Yajie Chen, Zhibin Xing, Guangqian Cao, Xin Cell Death Dis Article Oxysterol-binding protein like 2 (OSBPL2) was identified as a novel causal gene for autosomal dominant nonsyndromic hearing loss. However, the pathogenesis of OSBPL2 deficits in ADNSHL was still unclear. The function of OSBPL2 as a lipid-sensing regulator in multiple cellular processes suggested that OSBPL2 might play an important role in the regulation of cholesterol-homeostasis, which was essential for inner ear. In this study the potential roles of OSBPL2 in cholesterol biosynthesis and ROS production were investigated in Osbpl2-KO OC1 cells and osbpl2b-KO zebrafish. RNA-seq-based analysis suggested that OSBPL2 was implicated in cholesterol biosynthesis and AMPK signaling pathway. Furthermore, Osbpl2/osbpl2b-KO resulted in a reduction of AMPK activity and up-regulation of Srebp2/srebp2, Hmgcr/hmgcr and Hmgcs1/hmgcs1, key genes in the sterol biosynthetic pathway and associated with AMPK signaling. In addition, OSBPL2 was also found to interact with ATIC, key activator of AMPK. The levels of total cholesterol and ROS in OC1 cells or zebrafish inner ear were both increased in Osbpl2/osbpl2b-KO mutants and the mitochondrial damage was detected in Osbpl2-KO OC1 cells. This study uncovered the regulatory roles of OSBPL2 in cellular cholesterol biosynthesis and ROS production. These founds might contribute to the deep understanding of the pathogenesis of OSBPL2 mutation in ADNSHL. Nature Publishing Group UK 2019-08-19 /pmc/articles/PMC6700064/ /pubmed/31427568 http://dx.doi.org/10.1038/s41419-019-1858-9 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Wang, Hongshun
Lin, Changsong
Yao, Jun
Shi, Hairong
Zhang, Cui
Wei, Qinjun
Lu, Yajie
Chen, Zhibin
Xing, Guangqian
Cao, Xin
Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity
title Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity
title_full Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity
title_fullStr Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity
title_full_unstemmed Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity
title_short Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity
title_sort deletion of osbpl2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting ampk activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700064/
https://www.ncbi.nlm.nih.gov/pubmed/31427568
http://dx.doi.org/10.1038/s41419-019-1858-9
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