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

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 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.

Cholesterol 7α-hydroxylase-deficient mice are protected from high-fat/high-cholesterol diet-induced metabolic disorders

“…These mice had low survival rates and required vitamin supplementation to reach adulthood, and had reduced bile acid pool size, reduced fecal excretion of bile acids, and reduced fecal sterol and intestinal cholesterol absorption. It was also more recently reported that Cyp7a1 / mice exhibited induction of Cyp8b1 gene expression and repression of genes involved in the alternative synthesis pathway, and that these mice were physiologically responsive to low-dose CA and CDCA supplementation (19,20). The mice used in the present study were obtained by backcrossing the mixed background B6/129Sv strain with C57BL/6J mice for seven generations to obtain a nearly pure C57 background and represent a model suitable for use in dietary studies.…”

“…The original adult Cyp7a1 / mice in the mixed genetic background (B6/129Sv) had a reduced bile acid pool (30% of WT mice) and a normal lipid profile, while a later study of the same Cyp7a1 / mice (B6/129Sv) in a different colony demonstrated improved survival and a milder phenotype (18), though females in this colony were hypercholesterolemic. Two recent studies using the original Cyp7a1 / mice (B6/129Sv) demonstrated that even low dose bile acid feeding could rescue the knockout phenotype (19,20). These studies also reported that Cyp8b1 gene expression was upregulated in Cyp7a1 / mice (B6/129Sv), while genes involved in the alternative bile acid synthesis pathway were not, despite increased oxidized sterol content.…”

Molecular Properties of Guar Gum and Pectin Modify Cecal Bile Acids, Microbiota, and Plasma Lipopolysaccharide-Binding Protein in Rats

“…One study found that gut microbiota composition was altered in rats fed a single BA (cholic acid, CA) in a manner that was similar to those consuming a high-fat diet [ 6 ]. Supplementation with very low amounts of chenodeoxycholic acid (CDCA) also changed BA metabolism, highlighting the importance of diet in this process [ 7 ]. Other factors also influence the composition and metabolic activity of colonic microbiota: availability of nutrients—particularly dietary fiber (DF) and to some extent protein—is important for the formation of short-chain fatty acids (SCFAs), with different types of DF giving rise to different SCFA amounts and profiles during colonic fermentation [ 8 ].…”

MiRNA-17 encoded by the miR-17-92 cluster increases the potential for steatosis in hepatoma cells by targeting CYP7A1

“…They affect lipid responses to the lipid-lowering drug fenofibrate [ 32 ]. Mice deficient in CYP7A1 also exhibited changes in cholesterol and bile acid metabolism in the liver [ 33 ], while overexpression of CYP7A1 in the liver resulted in improved metabolic homeostasis in CYP7A1 transgenic mice [ 34 , 35 ].…”