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Journal of Lipid Research, Vol. 47, 1535-1541, July 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

The use of the Dhcr7 knockout mouse to accurately determine the origin of fetal sterols

G. S. Tint^1,2,*,, Hongwei Yu^1,, Quan Shang, Guorong Xu^*, and Shailendra B. Patel

^* Research Service, Department of Veterans Affairs Medical Center, East Orange, NJ 07018
Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103
Division of Endocrinology, Metabolism, and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, WI 53226

Published, JLR Papers in Press, May 1, 2006.

¹ G. S. Tint and H. Yu contributed equally to this work.

² To whom correspondence should be addressed. e-mail: tintgs{at}umdnj.edu

Mice with a targeted mutation of 3ß-hydroxysterol ⁷-reductase (Dhcr7) that cannot convert 7-dehydrocholesterol to cholesterol were used to identify the origin of fetal sterols. Because their heterozygous mothers synthesize cholesterol normally, virtually all sterols found in a Dhcr7 knockout fetus having a ⁷ or a ⁸ double bond must have been synthesized by the fetus itself but any cholesterol had to have come from the mother. Early in gestation, most fetal sterols were of maternal origin, but at approximately E13–14, in situ synthesis became increasingly important, and by birth, 55–60% of liver and lung sterols had been made by the fetus. In contrast, at E10–11, upon formation of the blood-brain barrier, the brain rapidly became the source of almost all of its own sterols (90% at birth). New, rapid, de novo sterol synthesis in brain was confirmed by the observation that concentrations of C24,25-unsaturated sterols were low in the brains of all very young fetuses but increased rapidly beginning at approximately E11–12. Reduced activity of sterol C24,25-reductase (Dhcr24) in brain, suggested by the abundance of C24,25-unsaturated compounds, seems to be the result of suppressed Dhcr24 expression. The early fetal brain also appears to conserve cholesterol by keeping cholesterol 24-hydroxylase expression low until approximately E18.

Supplementary key words Smith-Lemli-Opitz syndrome • desmosterol • sterol C24,25-reductase • cholesterol 24-hydroxylase • 7-dehydrocholesterol • 7-dehydrodesmosterol • development

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