Delineation of biochemical, molecular, and physiological changes accompanying bile acid pool size restoration in Cyp7a1^−/−mice fed low levels of cholic acid

Abstract

Jones RD, Repa JJ, Russell DW, Dietschy JM, Turley SD. Delineation of biochemical, molecular, and physiological changes accompanying bile acid pool size restoration in Cyp7a1 Ϫ/Ϫ mice fed low levels of cholic acid.

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

“…This was also the case in Cyp7a1 −/− mice maintained on a low-cholesterol diet containing either CDCA (Fig. 3C) or CA [31]. …”

“…Relative mRNA levels in individual animals were determined by expressing the amount of mRNA found relative to that obtained for Cyp7a1 +/+ mice fed the basal diet alone (all studies with males), or the basal diet enriched with cholesterol (studies with females), which in each case was arbitrarily set at 1.0. The primer sequences used to measure RNA levels for all genes have been reported in two earlier publications [31, 38]. The names of all genes studied are as follows; Cyp7a1, Cholesterol 7α-hydroxylase; Cyp27a1, Sterol 27-hydroxylase; Cyp39a1, Oxysterol 7α-hydroxylase; Cyp7b1, Oxysterol 7α-hydroxylase; Cyp8b1, Sterol 12α-hydroxylase; Abca1, ATP binding cassette member A1; Abcb11, Bile salt export pump (Bsep); Abcg5, ATP-binding cassette G5; Fabp6, Ileal bile acid binding protein (Ibabp); Fgf15, Fibroblast growth factor 15; Hmgcs, Hydroxymethylglutaryl coenzyme A synthase; Npc1l1, Niemann-Pick Type C1 -like 1; and Nr0b2, Short heterodimer partner (Shp).…”

“…The exploration of such putative new roles is often conducted using animal models in which BA metabolism is profoundly altered through the use of levels of dietary BA supplementation that cause pharmacological, rather than physiological shifts in BA synthesis and transport, as well as in the size and composition of the intestinal BA pool. This concern prompted our earlier studies where we used the cholesterol 7α-hydroxylase-deficient ( Cyp7a1 −/− ) mouse, which has an inherently small BA pool [29, 30], to investigate how pool replacement through the feeding of very low dietary levels of cholic acid (CA) impacted cholesterol and BA synthesis, storage and transport by the small intestine and liver at a biochemical and molecular level [31]. One reason why cholic acid was used first for pool restoration in this model is that CA mediates a clear regulatory effect on multiple aspects of cholesterol metabolism [32, 33].…”

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.…”