Abstract
AbstractThe 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.
Highlights
IntroductionUniversity of Massachusetts Medical School, Worcester, MA, USA. Current address for Ranjuna Weerasekera: Department of Molecular Biology and Biochemistry, Wesleyan University, Middletown, CT, USA
Medicine, University of Massachusetts Medical School, Worcester, MA, USA
The conversion of lanosterol to cholesterol has been described to occur via two main pathways, the Bloch pathway [1] and the Kandutsch-Russell pathway [2], which differ in whether reduction of the side chain C24-25 double bond occurs “first” or “last.” In the Kandutsch-Russell pathway the C24-C25 reduction takes place in the first step, whereas in the Bloch pathway this reduction occurs in the last step of the synthesis
Summary
University of Massachusetts Medical School, Worcester, MA, USA. Current address for Ranjuna Weerasekera: Department of Molecular Biology and Biochemistry, Wesleyan University, Middletown, CT, USA. The conversion of lanosterol to cholesterol has been described to occur via two main pathways, the Bloch pathway [1] and the Kandutsch-Russell pathway [2], which differ in whether reduction of the side chain C24-25 double bond occurs “first” or “last.” In the Kandutsch-Russell pathway the C24-C25 reduction takes place in the first step, whereas in the Bloch pathway this reduction occurs in the last step of the synthesis. Most commonly described as the enzyme catalyzing the conversion of desmosterol to cholesterol, DHCR24 can reduce the C24-25 double bond of any sterol intermediate, effectively switching sterol synthesis from the Bloch pathway to Kandutsch-Russell pathway This hybrid or modified Kandutsch-Russell pathway is likely how many (if not all) mammalian cells synthesize cholesterol, rather than by using one pathway exclusively [4, 5], and modifies the concept of first or last step.
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