Treatment of the cholesterol biosynthetic defect in Smith-Lemli-Opitz syndrome reproduced in rats by BM 15.766.
OBJECTIVE
The Smith-Lemli-Opitz syndrome is a recessive inherited disorder characterized by neurological developmental defects and dysmorphic features with a defect in cholesterol synthesis at the conversion of 7-dehydrocholesterol to cholesterol. BM 15.766 inhibits 7-dehydrocholesterol-delta 7-reductase and reproduces the biochemical defect. The aim of this study was to investigate the effects of cholesterol, cholic acid, and lovastatin feeding on rats fed BM 15.766.


METHODS
Plasma cholesterol and 7-dehydrocholesterol concentrations were related to the hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.


RESULTS
With the inhibitor treatment, plasma cholesterol concentrations decreased 67%; 7-dehydrocholesterol concentrations increased from trace to 17 mg/dL; and hepatic HMG-CoA reductase activity and messenger RNA levels were stimulated 74% and two times, respectively. In inhibitor-treated rats, feeding cholesterol increased plasma cholesterol concentrations 3.7 times, decreased 7-dehydrocholesterol concentrations 88%, and reduced elevated HMG-CoA reductase activity and messenger RNA levels 74% and 49%. Feeding cholic acid increased plasma cholesterol without reducing 7-dehydrocholesterol concentrations. The combination of cholic acid and cholesterol enhanced plasma cholesterol 9.5 times without decreasing 7-dehydrocholesterol levels. Feeding lovastatin depressed plasma cholesterol further without reducing 7-dehydrocholesterol levels.


CONCLUSIONS
Cholesterol is essential to correct abnormal cholesterol synthesis induced by BM 15.766 in rats by expanding the pool and inhibiting HMG-CoA reductase. Neither cholic acid nor lovastatin are effective separately, but cholic acid plus cholesterol may offer some additional benefit.
Xu
G
G
Department of Veterans Affairs Medical Center, East Orange, New Jersey, USA.
Salen
G
G
Shefer
S
S
Ness
G C
GC
Chen
T S
TS
Zhao
Z
Z
Salen
L
L
Tint
G S
GS
D000214:Acyl Coenzyme A / Q000032:analysis; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood / Q000627:therapeutic use*; D019826:Cholic Acid; D002793:Cholic Acids / Q000627:therapeutic use*; D003684:Dehydrocholesterols / Q000097:blood; D004195:Disease Models, Animal; D008099:Liver / Q000201:enzymology; D008148:Lovastatin / Q000627:therapeutic use*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019082:Smith-Lemli-Opitz Syndrome / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
D000214:Acyl Coenzyme A; D002793:Cholic Acids; D003684:Dehydrocholesterols; D010879:Piperazines; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; C047457:BM 15766; D002784:Cholesterol; D008148:Lovastatin; C016705:7-dehydrocholesterol; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase; D019826:Cholic Acid