Generation and validation of a conditional knockout mouse model for desmosterolosis

Journal of Lipid Research

Kirthi Pulakanti¹  Kriya S. Patel²  Roman Tyshynsky²  Shailendra B. Patel³  Vincent Fong³  Babunageswararao Kanuri³  Ranjuna Weerasekera⁴  Sithara Raju Ponny⁵ 

[1] Blood Research Institute, Versiti, Milwaukee, WI, USA;Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, WI, USA;Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, OH, USA;Division of Endocrinology, Medical College of Wisconsin, Milwaukee, WI, USA;Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;

关键词: DHCR24;    desmosterol;    liver;    dysmorphology;    cholesterol;    bile;   

DOI  :  

来源: DOAJ

【 摘 要 】

Abstract: 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 (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. 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.

【 授权许可】

Unknown