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

G. S. Tint, Hongwei Yu, Quan Shang, Guorong Xu, and Shailendra B. Patel

VA Medical Center, East Orange, NJ 07018

Corresponding Author: tintgs{at}umdnj.edu

Mice with a targeted mutation of Dhcr7 that cannot convert 7-dehydrocholesterol to cholesterol were employed to identify the origin of fetal sterols. Because their heterozygous mothers synthesize cholesterol normally, any cholesterol found in a Dhcr7 / fetus had to have come from its mother but all sterols having a 7- or a 8-double bond must have been synthesized by the fetus itself. Early in gestation most fetal sterols were of maternal origin but, at about 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 for 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 about E11-12. Reduced activity of 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 Cyp46A1 expression low until about E18.

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