PUBLICATION
Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity
- Authors
- Wang, H., Lin, C., Yao, J., Shi, H., Zhang, C., Wei, Q., Lu, Y., Chen, Z., Xing, G., Cao, X.
- ID
- ZDB-PUB-190821-2
- Date
- 2019
- Source
- Cell Death & Disease 10: 627 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- AMP-Activated Protein Kinases/antagonists & inhibitors*
- AMP-Activated Protein Kinases/metabolism
- Animals
- Cholesterol/biosynthesis*
- Gene Deletion
- Gene Knockout Techniques
- HEK293 Cells
- Hearing Loss/genetics*
- Hearing Loss/metabolism
- Humans
- Reactive Oxygen Species/metabolism*
- Receptors, Steroid/genetics*
- Receptors, Steroid/metabolism
- Signal Transduction
- Zebrafish
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- PubMed
- 31427568 Full text @ Cell Death Dis.
Citation
Wang, H., Lin, C., Yao, J., Shi, H., Zhang, C., Wei, Q., Lu, Y., Chen, Z., Xing, G., Cao, X. (2019) Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity. Cell Death & Disease. 10:627.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping