Marked reduction in bile acid synthesis in cholesterol 7α-hydroxylase- deficient mice does not lead to diminished tissue cholesterol turnover or to hypercholesterolemia

Margrit Schwarz, David W. Russell, John M. Dietschy, Stephen D. Turley

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192 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1833-1843
Number of pages11
JournalJournal of Lipid Research
Volume39
Issue number9
StatePublished - Sep 1998

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Cholesterol 7-alpha-Hydroxylase
Hypercholesterolemia
Bile Acids and Salts
Cholesterol
Tissue
Sterols
Cholates
Animals
Animal Structures
Intestinal Absorption
Metabolism
Liver
Weight Gain
Intestines
Triglycerides
Homeostasis
Genes
Body Weight
Plasmas

Keywords

  • Bile acid pool size
  • Cholesterol 7α-hydroxylase
  • Cholesterol absorption
  • Cholesterol synthesis
  • Liver
  • Small intestine

ASJC Scopus subject areas

  • Endocrinology

Cite this

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title = "Marked reduction in bile acid synthesis in cholesterol 7α-hydroxylase- deficient mice does not lead to diminished tissue cholesterol turnover or to hypercholesterolemia",
abstract = "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.",
keywords = "Bile acid pool size, Cholesterol 7α-hydroxylase, Cholesterol absorption, Cholesterol synthesis, Liver, Small intestine",
author = "Margrit Schwarz and Russell, {David W.} and Dietschy, {John M.} and Turley, {Stephen D.}",
year = "1998",
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pages = "1833--1843",
journal = "Journal of Lipid Research",
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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.

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

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KW - Small intestine

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