Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, OH, USA.
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
J Lipid Res. 2021;62:100028. doi: 10.1016/j.jlr.2021.100028. Epub 2021 Jan 30.
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 24 h from a lethal dermopathy, limiting its utility as a disease model. Here, we report a conditional KO mouse model (Dhcr24) and validate it by generating a liver-specific KO (Dhcr24). Dhcr24 mice showed normal growth and fertility, while accumulating significantly elevated levels of desmosterol in plasma and liver. Of interest, despite the loss of cholesterol synthesis in the liver, hepatic architecture, gene expression of sterol synthesis genes, and lipoprotein secretion appeared unchanged. The 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.
酶 3β-羟甾醇-Δ24 还原酶（DHCR24，EC 1.3.1.72）催化去甲胆固醇向胆固醇的转化，是鲨烯后胆固醇合成所必需的。该酶的遗传缺失导致去甲胆固醇血症（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（另一种鲨烯后胆固醇疾病）患者重叠。Dhcr24 在小鼠中的全局敲除（KO）再现了生化表型，但由于致命的皮肤病，幼鼠在 24 小时内死亡，限制了其作为疾病模型的用途。在这里，我们报告了一种条件性 KO 小鼠模型（Dhcr24），并通过生成肝脏特异性 KO（Dhcr24）对其进行了验证。Dhcr24 小鼠表现出正常的生长和生育能力，同时血浆和肝脏中去甲胆固醇水平显著升高。有趣的是，尽管肝脏中胆固醇合成丧失，但肝组织结构、固醇合成基因的基因表达和脂蛋白分泌似乎没有变化。胆汁和粪便中去甲胆固醇含量的增加表明肝肠分泌可能在维持固醇稳态方面发挥了代偿作用。这种小鼠模型现在应该允许研究 DHCR24 出生后缺失的影响，以及该酶在发育和成年期组织特异性缺失的作用。
