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. 2015 Jan:93:87-95.
doi: 10.1016/j.steroids.2014.11.002. Epub 2014 Nov 28.

Impact of physiological levels of chenodeoxycholic acid supplementation on intestinal and hepatic bile acid and cholesterol metabolism in Cyp7a1-deficient mice

Affiliations

Impact of physiological levels of chenodeoxycholic acid supplementation on intestinal and hepatic bile acid and cholesterol metabolism in Cyp7a1-deficient mice

Ryan D Jones et al. Steroids. 2015 Jan.

Abstract

Mice deficient in cholesterol 7α-hydroxylase (Cyp7a1) have a diminished bile acid pool (BAP) and therefore represent a useful model for investigating the metabolic effects of restoring the pool with a specific BA. Previously we carried out such studies in Cyp7a1(-/-) mice fed physiological levels of cholic acid (CA) and achieved BAP restoration, along with an increased CA enrichment, at a dietary level of just 0.03% (w/w). Here we demonstrate that in Cyp7a1(-/-) mice fed chenodeoxycholic acid (CDCA) at a level of 0.06% (w/w), the BAP was restored to normal size and became substantially enriched with muricholic acid (MCA) (>70%), leaving the combined contribution of CA and CDCA to be <15%. This resulted in a partial to complete reversal of the main changes in cholesterol and BA metabolism associated with Cyp7a1 deficiency such as an elevated rate of intestinal sterol synthesis, an enhanced level of mRNA for Cyp8b1 in the liver, and depressed mRNA levels for Ibabp, Shp and Fgf15 in the distal small intestine. When Cyp7a1(-/-) and matching Cyp7a1(+/+) mice were fed a diet with added cholesterol (0.2%) (w/w), either alone, or also containing CDCA (0.06%) (w/w) or CA (0.03%) (w/w) for 18days, the hepatic total cholesterol concentrations (mg/g) in the Cyp7a1(-/-) mice were 26.9±3.7, 16.4±0.9 and 47.6±1.9, respectively, vs. 4.9±0.4, 5.0±0.7 and 6.4±1.9, respectively in the corresponding Cyp7a1(+/+) controls. These data affirm the importance of using moderate levels of dietary BA supplementation to elicit changes in hepatic cholesterol metabolism through shifts in BAP size and composition.

Keywords: Bile acid pool composition; Cholesterol 7α-hydroxylase; Cholesterol absorption; Cholesterol synthesis; Hepatic cholesterol concentration; Muricholic acid.

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Figures

Fig. 1
Fig. 1
Bile acid pool size (A, B) and hepatic total cholesterol concentrations (C, D) in Cyp7a1+/+ and Cyp7a1−/− mice given varying levels of dietary chenodeoxycholic acid supplementation. The mice were fed their respective diets for 21 days. Values are the mean ± SEM, n=8 animals per group. Different letters above bars denote statistically significant differences between values (p < 0.05) as determined by one-way A NOVA.
Fig. 2
Fig. 2
Parameters of intestinal and hepatic cholesterol metabolism in Cyp7a1+/+ and Cyp7a1−/− mice given a fixed level of dietary chenodeoxycholic acid supplementation. Male mice were fed their respective diets for 15 to 18 days. The level of CDCA was 0.06% w/w. One set of animals was used to measure cholesterol absorption (A) and neutral sterol excretion (B), while a second set was used for determination of rates of intestinal (C) and hepatic (D) cholesterol synthesis. Values are the mean ± SEM, n=6 or 7 animals per group. Different letters above bars denote statistically significant differences between values (p < 0.05) as determined by one-way ANOVA.
Fig. 3
Fig. 3
Relative expression levels of mRNA for multiple genes in the liver and small intestine of Cyp7a1+/+ and Cyp7a1−/− mice given a fixed level of dietary chenodeoxycholic acid supplementation. The level of CDCA was 0.06% w/w. These tissues were from the male mice used for the cholesterol absorption and sterol excretion measurements. The gene names are given in Materials and Methods. Relative mRNA levels in individual animals were determined by expressing of the amount of mRNA found relative to that obtained for Cyp7a1+/+ mice not given bile acid supplementation which was arbitrarily set at 1.0. Values are the mean ± SEM, n=5 animals per group. Different letters above bars denote statistically significant differences between values (p < 0.05) as determined by one-way ANOVA.
Fig. 4
Fig. 4
Comparison of effect of dietary supplementation with either chenodeoxycholic or cholic acid on hepatic total cholesterol concentrations in Cyp7a1+/+ and Cyp7a1−/− mice fed diets without and with added cholesterol. Female Cyp7a1+/+ and Cyp7a1−/− mice were fed for 18 days either the basal diet alone, or containing added cholest e rol (0.2% w/w), along with either CDCA or CA at a level known to be sufficient to fully restore BA pool size in Cyp7a 1−/− mice (Fig. 1B for CDCA, and Reference [31] for CA). Values are the mean ± SEM, n=5 animals per group. Within the groups given diets either without or with added cholesterol, different letters above bars denote statistically significant differences between values (p < 0.05), as determined by one-way ANOVA.
Fig. 5
Fig. 5
Relative expression levels of mRNA for multiple genes in the livers of cholesterol-fed Cyp7a1+/+ and Cyp7a1−/− mice given fixed levels of either chenodeoxycholic or cholic acid supplementation. The liver tissue for these analyses was derived from the same mice used in the study described in Fig. 4C and D. mRNA levels in individual animals were determined by expressing the amount of mRNA found relative to that obtained for Cyp7a1+/+ mice given the cholesterol-enriched diet but without any bile acid supplementation. Values are mean ± SEM, n=5 animals per group. Different letters above bars denote statistically significant differences between values (p < 0.05) as determined by one-way ANOVA.

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