Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity
| Autor: | Yajie Lu, Guangqian Xing, Jun Yao, Zhibin Chen, Qinjun Wei, Xin Cao, Changsong Lin, Cui Zhang, Hairong Shi, Hongshun Wang |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Receptors Steroid Cancer Research Immunology AMP-Activated Protein Kinases Biology Article Gene Knockout Techniques 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Biosynthesis Animals Humans Clinical genetics lcsh:QH573-671 Hearing Loss Zebrafish chemistry.chemical_classification Reactive oxygen species lcsh:Cytology Activator (genetics) HEK 293 cells AMPK Cell Biology Zebrafish Proteins biology.organism_classification Sterol Cell biology Cholesterol HEK293 Cells 030104 developmental biology chemistry lipids (amino acids peptides and proteins) Signal transduction Reactive Oxygen Species Gene Deletion 030217 neurology & neurosurgery Cell signalling Signal Transduction |
| Zdroj: | Cell Death and Disease, Vol 10, Iss 9, Pp 1-13 (2019) Cell Death & Disease |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/s41419-019-1858-9 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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