OSBPL2-disrupted pigs recapitulate dual features of human hearing loss and hypercholesterolaemia

Yao, Jun; Zeng, Huasha; Zhang, Min; Wei, Qinjun; Wang, Ying; Yang, Haiyuan; Lu, Yajie; Li, Rongfeng; Xiong, Qiang; Zhang, Lining; Chen, Zhibin; Xing, Guangqian; Cao, Xin; Dai, Yifan

doi:10.1016/j.jgg.2019.06.006

Cited by 23 publications

(23 citation statements)

References 38 publications

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“…To confirm the consistent effect of OSBPL2/ORP2 in hearing loss by both genotype and phenotype, we successfully simulated human hearing loss phenotypes in both Bama mini pig and zebrafish models. Especially in the OSBPL2 -disrupted pigs, we reproduced not only a deafness phenotype similar to that of humans but also a hypercholesterolemia phenotype ( Yao et al., 2019 ). In subsequent studies of OSBPL2/ORP2 functions, we found that OSBPL2 was downregulated by 25-hydroxycholesterol ( Wang et al., 2019c ).…”

Section: Discussionmentioning

confidence: 79%

“…The results from our previous study showed that OSBPL2 −/− Bama mini pigs exhibited obvious obesity and hypercholesterolemia phenotypes ( Yao et al., 2019 ), and the established adult osbpl2b −/− zebrafish have also shown abnormal lipid-metabolism-related characteristics. The osbpl2b −/− zebrafish in this study were used to test whether altered osbpl2b disturbs energy homeostasis in vivo .…”

Section: Resultsmentioning

confidence: 97%

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OSBPL2 Is Required for the Binding of COPB1 to ATGL and the Regulation of Lipid Droplet Lipolysis

et al. 2020

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Summary The accumulation of giant lipid droplets (LDs) increases the risk of metabolic disorders including obesity and insulin resistance. The lipolysis process involves the activation and transfer of lipase, but the molecular mechanism is not completely understood. The translocation of ATGL, a critical lipolysis lipase, from the ER to the LD surface is mediated by an energy catabolism complex. Oxysterol-binding protein-like 2 (OSBPL2/ORP2) is one of the lipid transfer proteins that regulates intracellular cholesterol homeostasis. A recent study has proven that Osbpl2 −/− pigs exhibit hypercholesterolemia and obesity phenotypes with an increase in adipocytes. In this study, we identified that OSBPL2 links the endoplasmic reticulum (ER) with LDs, binds to COPB1, and mediates ATGL transport. We provide important insights into the function of OSBPL2, indicating that it is required for the regulation of lipid droplet lipolysis.

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Section: Discussionmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 97%

OSBPL2 Is Required for the Binding of COPB1 to ATGL and the Regulation of Lipid Droplet Lipolysis

et al. 2020

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“…OSBPL2 is a lipid binding protein that is an important regulator of intracellular cholesterol homeostasis through lipid metabolism and transport. Knockout OSBPL2 bama miniature pigs have hypercholesterolemia, increase in adipocytes, with obesity phenotypes [85]. The link between decreased OSBPL2 expression and obesity in an animal model is interesting given obesity is a known epidemiological risk factor for canine ACL rupture and two of the chromosome 24 CNVRs were deletions.…”

Section: Plos Onementioning

confidence: 99%

Analysis of copy number variation in dogs implicates genomic structural variation in the development of anterior cruciate ligament rupture

et al. 2020

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Anterior cruciate ligament (ACL) rupture is an important condition of the human knee. Second ruptures are common and societal costs are substantial. Canine cranial cruciate ligament (CCL) rupture closely models the human disease. CCL rupture is common in the Labrador Retriever (5.79% prevalence), ~100-fold more prevalent than in humans. Labrador Retriever CCL rupture is a polygenic complex disease, based on genome-wide association study (GWAS) of single nucleotide polymorphism (SNP) markers. Dissection of genetic variation in complex traits can be enhanced by studying structural variation, including copy number variants (CNVs). Dogs are an ideal model for CNV research because of reduced genetic variability within breeds and extensive phenotypic diversity across breeds. We studied the genetic etiology of CCL rupture by association analysis of CNV regions (CNVRs) using 110 case and 164 control Labrador Retrievers. CNVs were called from SNPs using three different programs (PennCNV, CNVPartition, and QuantiSNP). After quality control, CNV calls were combined to create CNVRs using ParseCNV and an association analysis was performed. We found no strong effect CNVRs but found 46 small effect (max(T) permutation P<0.05) CCL rupture associated CNVRs in 22 autosomes; 25 were deletions and 21 were duplications. Of the 46 CCL rupture associated CNVRs, we identified 39 unique regions. Thirty four were identified by a single calling algorithm, 3 were identified by two calling algorithms, and 2 were identified by all three algorithms. For 42 of the associated CNVRs, frequency in the population was <10% while 4 occurred at a frequency in the population ranging from 10–25%. Average CNVR length was 198,872bp and CNVRs covered 0.11 to 0.15% of the genome. All CNVRs were associated with case status. CNVRs did not overlap previous canine CCL rupture risk loci identified by GWAS. Associated CNVRs contained 152 annotated genes; 12 CNVRs did not have genes mapped to CanFam3.1. Using pathway analysis, a cluster of 19 homeobox domain transcript regulator genes was associated with CCL rupture (P = 6.6E-13). This gene cluster influences cranial-caudal body pattern formation during embryonic limb development. Clustered genes were found in 3 CNVRs on chromosome 14 (HoxA), 28 (NKX6-2), and 36 (HoxD). When analysis was limited to deletion CNVRs, the association was strengthened (P = 8.7E-16). This study suggests a component of the polygenic risk of CCL rupture in Labrador Retrievers is associated with small effect CNVs and may include aspects of stifle morphology regulated by homeobox domain transcript regulator genes.

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“…These mutations are functionally deleterious because ORP2 is expressed with a truncated or absent ORD. Recently, an ORP2 knockout (KO) pig model provided insight into the mechanism of hearing loss (Yao et al., 2019). Inner and outer hair cells of ORP2 KO pigs had degenerated or absent stereocilia morphology and increased levels of apoptosis.…”

Section: Oxysterol Binding Protein-related Protein 2 (Orp2)mentioning

confidence: 99%

ORP1L, ORP1S, and ORP2: Lipid Sensors and Transporters

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et al. 2020

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Lipid transfer proteins are crucial for intracellular cholesterol trafficking at sites of membrane contact. In the OSBP/ORPs (oxysterol binding protein and OSBP-related proteins) family of lipid transfer proteins, ORP1L, ORP1S and ORP2 play important roles in cholesterol transport. ORP1L is an endosome/lysosome-anchored cholesterol sensor which may also move cholesterol bidirectionally at the interface between the endoplasmic reticulum and the endosome/lysosome. ORP2 delivers cholesterol to the plasma membrane, driven by PI(4,5)P2 hydrolysis. ORP1S may also transport cholesterol to the plasma membrane, although it is unclear if phosphoinositides are involved. The source of cholesterol delivered to the plasma membrane by ORP1S and ORP2 remains unclear. This review summarises the roles of these proteins in maintaining cellular cholesterol homeostasis and in human disease.

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OSBPL2-disrupted pigs recapitulate dual features of human hearing loss and hypercholesterolaemia

Cited by 23 publications

References 38 publications

OSBPL2 Is Required for the Binding of COPB1 to ATGL and the Regulation of Lipid Droplet Lipolysis

OSBPL2 Is Required for the Binding of COPB1 to ATGL and the Regulation of Lipid Droplet Lipolysis

Analysis of copy number variation in dogs implicates genomic structural variation in the development of anterior cruciate ligament rupture

ORP1L, ORP1S, and ORP2: Lipid Sensors and Transporters

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