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Generation and validation of a conditional knockout mouse model for Desmosterolosis.
Journal of Lipid Research ( IF 6.5 ) Pub Date : 2021-01-29 , DOI: 10.1016/j.jlr.2021.100028
Babunageswararao Kanuri 1 , Vincent Fong 1 , Sithara Raju Ponny 2 , Ranjuna Weerasekera 3 , Kirthi Pulakanti 4 , Kriya S Patel 5 , Roman Tyshynsky 5 , Shailendra B Patel 6
Affiliation  

The enzyme 3β-hydroxysterol-Δ24 reductase (DHCR24, EC 1.3.1.72) catalyzes the conversion of desmosterol to cholesterol, and is obligatory for post-squalene cholesterol synthesis. Genetic loss of this enzyme results in Desmosterolosis (MIM #602398), a rare disease that presents with multiple congenital anomalies, features of which overlap with subjects with the Smith-Lemli-Opitz syndrome (another post-squalene cholesterol disorder). Global knockout (KO) of Dhcr24 in mice recapitulates the biochemical phenotype, but pups die within 24h from a lethal dermopathy, limiting its utility as a disease model. Here, we report a conditional KO mouse model (Dhcr24flx/flx) and validate it by generating a liver-specific KO (Dhcr24flx/flx,Alb-Cre). Dhcr24flx/flx,Alb-Cre mice showed normal growth and fertility, while accumulating significantly elevated levels of desmosterol in plasma and liver. Interestingly, despite the loss of cholesterol synthesis in the liver, hepatic architecture, gene expression of sterol synthesis genes and lipoprotein secretion appeared unchanged. Increased desmosterol content in bile and stool indicated a possible compensatory role of hepatobiliary secretion in maintaining sterol homeostasis. This mouse model should now allow for the study of the effects of postnatal loss of DHCR24, as well as role of tissue-specific loss of this enzyme during development and adulthood.

中文翻译:

Desmosterolosis 条件性敲除小鼠模型的生成和验证。

酶 3β-羟基甾醇-Δ24 还原酶 (DHCR24, EC 1.3.1.72) 催化去甾醇转化为胆固醇,并且是角鲨烯胆固醇合成所必需的。这种酶的遗传缺失导致 Desmosterolosis (MIM #602398),这是一种罕见的疾病,表现为多种先天性异常,其特征与 Smith-Lemli-Opitz 综合征(另一种角鲨烯后胆固醇疾病)的受试者重叠。小鼠中 Dhcr24 的全局敲除 (KO) 概括了生化表型,但幼崽在 24 小时内死于致命的皮肤病,限制了其作为疾病模型的实用性。在这里,我们报告了一个条件 KO 小鼠模型 (Dhcr24 flx/flx ) 并通过生成肝脏特异性 KO (Dhcr24 flx/flx,Alb-Cre ) 对其进行验证。Dhcr24 flx/flx,Alb-Cre小鼠表现出正常的生长和生育能力,同时血浆和肝脏中的去甾醇水平显着升高。有趣的是,尽管肝脏中胆固醇合成的损失,肝脏结构、甾醇合成基因的基因表达和脂蛋白分泌似乎没有变化。胆汁和粪便中地甾醇含量的增加表明肝胆分泌在维持甾醇稳态中可能具有补偿作用。这种小鼠模型现在应该允许研究 DHCR24 出生后丢失的影响,以及这种酶在发育和成年期间组织特异性丢失的作用。
更新日期:2021-02-03
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