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dc.contributor.authorChen, Li-Jie
dc.contributor.authorLin, Xiu-Xian
dc.contributor.authorGuo, Jing
dc.contributor.authorXu, Ying
dc.contributor.authorZhang, Song-Xia
dc.contributor.authorChen, Dan
dc.contributor.authorZhao, Qing
dc.contributor.authorXiao, Jian
dc.contributor.authorLian, Guang-Hui
dc.contributor.authorPeng, Shi-Fang
dc.contributor.authorGuo, Dong
dc.contributor.authorYang, Hong
dc.contributor.authorShu, Yan
dc.contributor.authorZhou, Hong-Hao
dc.contributor.authorZhang, Wei
dc.contributor.authorChen, Yao
dc.date.accessioned2021-10-28T18:07:22Z
dc.date.available2021-10-28T18:07:22Z
dc.date.issued2021-09-21
dc.identifier.urihttp://hdl.handle.net/10713/17004
dc.description.abstractBackground: Nonalcoholic fatty liver disease (NAFLD) is a serious threat to human health worldwide, with a high genetic susceptibility. Rs2302685, a functional germline variant of LRP6, has been recently found to associate with NAFLD risk. This study was aimed to clarify the underlying mechanism associated with rs2302685 risk and its impact on pharmacotherapy in treatment of NAFLD. Methods: Venous blood samples were collected from NAFLD and non-NAFLD patients for SNP genotyping by using mass spectrometry. The Lrp6-floxdel mouse (Lrp6 (+/-)) was generated to model the partial function associated with human rs2302685. The liver injury and therapeutic effects of silibinin were compared between Lrp6 (+/-) and Lrp6 (+/+) mice received a methionine-choline deficient (MCD) diet or normal diet. The effect of Lrp6 functional alteration on Wnt/β-catenin-Cyp2e1 signaling activities was evaluated by a series of cellular and molecular assays. Results: The T allele of LRP6 rs2302685 was confirmed to associate with a higher risk of NAFLD in human subjects. The carriers of rs2302685 had reduced level of AST and ALT as compared with the noncarriers. The Lrp6 (+/-) mice exhibited a less severe liver injury induced by MCD but a reduced response to the treatment of silibinin in comparison to the Lrp6 (+/+) mice, suggesting Lrp6 as a target of silibinin. Wnt/β-catenin-Cyp2e1 signaling together with ROS generation could be exacerbated by the overexpression of Lrp6, while decreased in response to Lrp6 siRNA or silibinin treatment under NAFLD modeling. Conclusions: The Lrp6 function affects individual susceptibility to NAFLD and the therapeutic effect of silibinin through the Wnt/β-catenin-Cyp2e1 signaling pathway. The present work has provided an underlying mechanism for human individual susceptibility to NAFLD associated with Lrp6 polymorphisms as well as a rationale for the effective use of silibinin in NAFLD patients.en_US
dc.description.urihttps://doi.org/10.7150/ijbs.63732en_US
dc.description.urihttp://www.ncbi.nlm.nih.gov/pmc/articles/pmc8495406/en_US
dc.language.isoenen_US
dc.publisherIvyspring International Publisheren_US
dc.relation.ispartofInternational Journal of Biological Sciencesen_US
dc.rights© The author(s).en_US
dc.subjectcytochrome P450 2e1en_US
dc.subjectgenotypeen_US
dc.subjectlow-density lipoprotein receptor-related protein 6en_US
dc.subjectnonalcoholic fatty liver diseaseen_US
dc.subjectreactive oxygen speciesen_US
dc.titleLrp6 Genotype affects Individual Susceptibility to Nonalcoholic Fatty Liver Disease and Silibinin Therapeutic Response via Wnt/β-catenin-Cyp2e1 Signalingen_US
dc.typeArticleen_US
dc.identifier.doi10.7150/ijbs.63732
dc.identifier.pmid34671210
dc.source.volume17
dc.source.issue14
dc.source.beginpage3936
dc.source.endpage3953
dc.identifier.eissn1449-2288
dc.source.countryAustralia
dc.identifier.journalInternational journal of biological sciences


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