Abstract
We investigated the effect of ileal bile acid transport on the regulation of classic and alternative bile acid synthesis in cholesterol-fed rats and rabbits. Bile acid pool sizes, fecal bile acid outputs (synthesis rates), and the activities of cholesterol 7α-hydroxylase (classic bile acid synthesis) and cholesterol 27-hydroxylase (alternative bile acid synthesis) were related to ileal bile acid transporter expression (ileal apical sodium-dependent bile acid transporter, ASBT). Plasma cholesterol levels rose 2.1-times in rats (98 ± 19 mg/dl) and 31-times (986 ± 188 mg/dl) in rabbits. The bile acid pool size remained constant (55 ± 17 mg vs. 61 ± 18 mg) in rats but doubled (254 ± 46 to 533 ± 53 mg) in rabbits. ASBT protein expression did not change in rats but rose 31% (P < 0.05) in rabbits. Fecal bile acid outputs that reflected bile acid synthesis increased 2- and 2.4-times (P < 0.05) in cholesterol-fed rats and rabbits, respectively. Cholesterol 7α-hydroxylase activity rose 33% (24 ± 2.4 vs. 18 ± 1.6 pmol/mg/min, P < 0.01) and mRNA levels increased 50% (P < 0.01) in rats but decreased 68% and 79%, respectively, in cholesterol-fed rabbits. Cholesterol 27-hydroxylase activity remained unchanged in rats but rose 62% (P < 0.05) in rabbits. Classic bile acid synthesis (cholesterol 7α-hydroxylase) was inhibited in rabbits because an enlarged bile acid pool developed from enhanced ileal bile acid transport. In contrast, in rats, cholesterol 7α-hydroxylase was stimulated but the bile acid pool did not enlarge because ASBT did not change. Therefore, although bile acid synthesis was increased via different pathways in rats and rabbits, enhanced ileal bile acid transport was critical for enlarging the bile acid pool size that exerted feedback regulation on cholesterol 7α-hydroxylase in rabbits. —Xu, G., B. L. Shneider, S. Shefer, L. B. Nguyen, A. K. Batta, G. S. Tint, M. Arrese, S. Thevananther, L. Ma, S. Stengelin, W. Kramer, D. Greenblatt, M. Pcolinsky, and G. Salen. Ileal bile acid transport regulates bile acid pool, synthesis, and plasma cholesterol levels differently in cholesterol-fed rats and rabbits.
Highlights
We investigated the effect of ileal bile acid transport on the regulation of classic and alternative bile acid synthesis in cholesterol-fed rats and rabbits
The results demonstrated that cholesterol stimulated cholesterol 7␣-hydroxylase activity and mRNA levels without changing the bile acid pool size in rats
Cholesterol-fed rabbits showed inhibited cholesterol 7␣hydroxylase activity and mRNA levels probably due to an expanded bile acid pool. These differences may be related to ileal bile acid reabsorption as ileal apical sodium-dependent bile acid transporter (ASBT) protein increased 31% in cholesterol-fed rabbits but remained unchanged in rats after cholesterol feeding
Summary
We investigated the effect of ileal bile acid transport on the regulation of classic and alternative bile acid synthesis in cholesterol-fed rats and rabbits. Ileal bile acid transport regulates bile acid pool, synthesis, and plasma cholesterol levels differently in cholesterol-fed rats and rabbits. It is well known that feeding cholesterol to rats up-regulates both activity and mRNA levels of cholesterol 7␣-hydroxylase [5,6,7], the rate-controlling enzyme for the classic bile acid synthetic pathway. We hypothesized that the increased bile acid pool size not cholesterol was responsible for the inhibition of cholesterol 7␣-hydroxylase in cholesterol-fed rabbits. By gradually increasing the intake of dietary cholesterol in rabbits, we showed an inverse relationship between the size of the bile acid pool and cholesterol 7␣-hydroxylase activity [15]. The exact role that ILBP plays remains controversial and the effect of cholesterol feeding on ILBP has not yet been examined
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