REPRODUCING ABNORMAL CHOLESTEROL-BIOSYNTHESIS AS SEEN IN THE SMITH-LEMLI-OPITZ SYNDROME BY INHIBITING THE CONVERSION OF 7-DEHYDROCHOLESTEROL TO CHOLESTEROL IN RATS
Gr. Xu et al., REPRODUCING ABNORMAL CHOLESTEROL-BIOSYNTHESIS AS SEEN IN THE SMITH-LEMLI-OPITZ SYNDROME BY INHIBITING THE CONVERSION OF 7-DEHYDROCHOLESTEROL TO CHOLESTEROL IN RATS, The Journal of clinical investigation, 95(1), 1995, pp. 76-81
The Smith-Lemli-Opitz syndrome is a recessive inherited disorder chara
cterized by neurologic developmental defects and dysmorphic features i
n many organs. Recently, abnormal cholesterol biosynthesis with impair
ed conversion of 7-dehydrocholesterol to cholesterol has been discover
ed in homozygotes, To reproduce the biochemical abnormality, BM 15.766
, a competitive inhibitor of 7-dehydrocholesterol-Delta(7)-reductase,
the enzyme that catalyzes the conversion of 7-dehydrocholesterol into
cholesterol was fed by gavage to rats. After 14 d, plasma cholesterol
concentrations declined from 48 mg/dl to 16 mg/dl and 7-dehydro-choles
terol levels rose from trace to 17 mg/dl, Hepatocytes surrounding the
central vein developed balloon necrosis. Stimulating cholesterol synth
esis with cholestyramine followed by BM 15.766 produced an additional
40% decline (P < 0.05) in plasma cholesterol and 34% increase in 7-deh
ydrocholesterol levels compared to the inhibitor alone. Adding 2% chol
esterol to the diet during the second week of BM 15.766 treatment incr
eased plasma cholesterol threefold and decreased 7-dehydrocholesterol
concentrations 55%. Hepatic 3-hydroxy-3-methylglutaryl co-enzyme A (HM
G-CoA) reductase activity increased 73% with a 3.9-fold rise in mRNA l
evels but cholesterol 7 alpha-hydroxylase activity decreased slightly
though mRNA levels increased 1.4 times with BM 15.766 treatment. These
results demonstrate that BM 15.766 is a potent inhibitor of 7-dehydro
cholesterol-Delta(7)-reductase. The model reproduces abnormal choleste
rol biosynthesis as seen in the Smith-Lemli-Opitz syndrome and is usef
ul to test different treatment strategies. Stimulating early steps of
cholesterol synthesis worsens the biochemical abnormalities while feed
ing cholesterol inhibits abnormal synthesis, improves the biochemical
abnormalities and prevents liver damage.