Hepatic isoprenoid metabolism in a rat model of Smith-Lemli-Opitz Syndrome.
Elevated (4 to 7-fold) levels of urinary dolichol and coenzyme Q and substantially longer chain lengths for urinary dolichols have been reported in Smith-Lemli-Opitz Syndrome (SLOS) patients, compared to normal subjects. We investigated the possibility of similar alterations in hepatic, nonsterol isoprenoids in a well-established rat model of SLOS. In this model, the ratio of 7-dehydrocholesterol (7DHC) to cholesterol (Chol) in serum approached 15:1; however, total sterol mass in serum decreased by >80 %. Livers from treated rats had 7DHC/Chol ratios of ~32:1, but the steady-state levels of total sterols were >40 % those of livers from age-matched (3-month-old) control animals. No significant differences in the levels of LDL receptor or HMG-CoA reductase were observed. The levels of dolichol and coenzyme Q were elevated only modestly (by 64 and 31 %, respectively; p < 0.05, N = 6) in the livers of the SLOS rat model compared to controls; moreover, the chain lengths of these isoprenoids were not different in the two groups. We conclude that hepatic isoprenoid synthesis is marginally elevated in this animal model of SLOS, but without preferential shunting to the nonsterol branches (dolichol and coenzyme Q) of the pathway and without alteration of normal dolichol chain lengths.
Department of Molecular Medicine, University of South Florida, College of Medicine, Tampa, FL 33612, USA.
R Kennedy
RK
Keller
David A
DA
Mitchell
Christopher C
CC
Goulah
Steven J
SJ
Fliesler
D000818:Animals; D000924:Anticholesteremic Agents; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D003684:Dehydrocholesterols / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D004286:Dolichols / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D019082:Smith-Lemli-Opitz Syndrome / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D013729:Terpenes / Q000097:blood / Q000378:metabolism*; D014451:Ubiquinone / Q000378:metabolism; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride
D000924:Anticholesteremic Agents; D003684:Dehydrocholesterols; D004286:Dolichols; D013729:Terpenes; D014451:Ubiquinone; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride; D002784:Cholesterol; C016705:7-dehydrocholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase