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

• Mice efficiently convert chenodeoxycholic acid (CDCA) to muricholic acid (MCA).
• Bile acid (BA) pool size is diminished in cholesterol 7α-hydroxylase-deficient mice.
• A dietary CDCA level of just 0.06% (w/w) normalizes BA pool size in Cyp7a1−/− mice.
• MCA displaces cholic acid as the dominant BA in the pool of Cyp7a1−/− mice fed CDCA.
• Hepatic cholesterol levels in cholesterol-fed Cyp7a1−/− mice rise less with CDCA.

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 18 days, 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.