TY - JOUR
T1 - Marked reduction in bile acid synthesis in cholesterol 7α-hydroxylase- deficient mice does not lead to diminished tissue cholesterol turnover or to hypercholesterolemia
AU - Schwarz, Margrit
AU - Russell, David W.
AU - Dietschy, John M.
AU - Turley, Stephen D.
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 1998/9
Y1 - 1998/9
N2 - These studies used mice that were deficient in cholesterol 7α- hydroxylase to determine the effects of reduced bile acid synthesis on cholesterol homeostasis. In mice lacking this enzyme, bile acid synthesis was reduced from 8.3 to 3.4 μmol/day per 100 g body weight, the intestinal bile acid pool was decreased from 62.5 to 13.2 μmol/100 g bw, and the proportion of hyodeoxycholate, relative to cholate, in this pool was significantly increased. Associated with these changes, intestinal cholesterol absorption decreased from 37% to <1% while triacylglycerol absorption and animal weight gain remained essentially unaffected. The very low rate of cholesterol absorption could be corrected by feeding the mutant mice cholate, but not hyodeoxycholate. The reduction in sterol uptake across the intestine was associated with a 2-fold increase in cholesterol synthesis in the small bowel and liver and an increase in fecal neutral sterol excretion from 15.2 to 35.7 μmol/day per 100 g bw. The size of the cholesterol pools in the plasma, various organs and whole animal remained constant. Thus, under circumstances where the excretion of sterol as bile acids was markedly reduced, total cholesterol turnover actually increased from 164 to 239 mg/day per kg bw. This study demonstrates the complex interactions between bile acid and cholesterol metabolism and the dramatic effects of eliminating a single gene product; however, even though a major catabolic pathway was deleted, cholesterol balance across the animal was maintained.
AB - These studies used mice that were deficient in cholesterol 7α- hydroxylase to determine the effects of reduced bile acid synthesis on cholesterol homeostasis. In mice lacking this enzyme, bile acid synthesis was reduced from 8.3 to 3.4 μmol/day per 100 g body weight, the intestinal bile acid pool was decreased from 62.5 to 13.2 μmol/100 g bw, and the proportion of hyodeoxycholate, relative to cholate, in this pool was significantly increased. Associated with these changes, intestinal cholesterol absorption decreased from 37% to <1% while triacylglycerol absorption and animal weight gain remained essentially unaffected. The very low rate of cholesterol absorption could be corrected by feeding the mutant mice cholate, but not hyodeoxycholate. The reduction in sterol uptake across the intestine was associated with a 2-fold increase in cholesterol synthesis in the small bowel and liver and an increase in fecal neutral sterol excretion from 15.2 to 35.7 μmol/day per 100 g bw. The size of the cholesterol pools in the plasma, various organs and whole animal remained constant. Thus, under circumstances where the excretion of sterol as bile acids was markedly reduced, total cholesterol turnover actually increased from 164 to 239 mg/day per kg bw. This study demonstrates the complex interactions between bile acid and cholesterol metabolism and the dramatic effects of eliminating a single gene product; however, even though a major catabolic pathway was deleted, cholesterol balance across the animal was maintained.
KW - Bile acid pool size
KW - Cholesterol 7α-hydroxylase
KW - Cholesterol absorption
KW - Cholesterol synthesis
KW - Liver
KW - Small intestine
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M3 - Article
C2 - 9741696
AN - SCOPUS:0031705644
SN - 0022-2275
VL - 39
SP - 1833
EP - 1843
JO - Journal of lipid research
JF - Journal of lipid research
IS - 9
ER -