Impact of Inhibiting Ileal Apical versus Basolateral Bile Acid Transport on Cholesterol Metabolism and Atherosclerosis in Mice

Abstract

Background: Bile acid sequestrants have been used for many years to treat hypercholesterolemia by increasing hepatic conversion of cholesterol to bile acids, thereby inducing hepatic LDL receptor expression and clearance of apoB-containing particles. In order to further understand the underlying molecular mechanisms linking gut-liver signaling and cholesterol homeostasis, mouse models defective in ileal apical membrane bile acid transport (Asbt-null) and ileal basolateral membrane bile acid transport (Ostα-null) were studied under basal and hypercholesterolemic conditions. Key Messages: Hepatic conversion of cholesterol to bile acids is the major pathway for cholesterol catabolism and a major mechanism for cholesterol elimination. Blocking ileal apical membrane bile acid transport (Asbt-null mice) increases fecal bile acid excretion, hepatic Cyp7a1 expression, and the relative proportion of taurocholate in the bile acid pool, but decreases ileal FGF15 expression, bile acid pool size, and hepatic cholesterol content. In contrast, blocking ileal basolateral membrane bile acid transport (Ostα-null mice) increases ileal FGF15 expression, reduces hepatic Cyp7a1 expression, and increases the proportion of tauro-β-muricholic acid in the bile acid pool. In the hypercholesterolemic apoE-null background, plasma cholesterol levels and measurements of atherosclerosis were reduced in Asbt/apoE-null mice, but not in Ostα/apoE-null mice. Conclusions: Blocking the intestinal absorption of bile acids at the apical versus basolateral membrane differentially affects bile acid and cholesterol metabolism, including the development of hypercholesterolemia-associated atherosclerosis. The molecular mechanism likely involves an altered regulation of ileal FGF15 expression.

Efficient reabsorption of transintestinally excreted cholesterol is a strong determinant for cholesterol disposal in mice

“…We showed that Asbt -/mice had a 3-fold increase in fecal BA and NS excretion. While it was previously reported that Asbt -/mice have decreased fractional cholesterol absorption (55% versus 74% in WT littermates) (12), it remained unclear whether this could quantitatively account for the strongly increased fecal NS excretion (17,39). Our data show that fractional cholesterol absorption in Asbt -/mice was much lower (~6%), and even similar to that of WT mice treated with ezetimibe (~4%), suggesting that the increase in fecal NS excretion was mainly due to impaired cholesterol (re)absorption.…”

“…For ezetimibe, the mechanism of inhibition of cholesterol (re)absorption has been directly related to inhibition of NPC1L1, the main protein responsible for cholesterol absorption (38). For Asbt -/inactivation, however, the mechanism of decreased cholesterol (re)absorption has been less clear (39).…”

Attenuation of the Hepatoprotective Effects of Ileal Apical Sodium Dependent Bile Acid Transporter (ASBT) Inhibition in Choline-Deficient L-Amino Acid-Defined (CDAA) Diet-Fed Mice

“…We previously reported that genetic ASBT knockout in mice reduces intestinal fat and cholesterol absorption (29,34,35). In order to determine if the ASBTi treatment had similar effects in the CSAA and CDAA diet-fed mice, we measured fat absorption using the sucrose polybehenate method (20).…”

Effect of single and multiple doses of elobixibat, an ileal bile acid transporter inhibitor, on chronic constipation: A randomized controlled trial

“…http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9996 (rINN) is a highly selective inhibitor of an http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=182#960, leading to augmentation of BA levels in the colon and subsequently enhancing colonic motility and secretion 12. In addition, reduced ileal BA reabsorption upregulates hepatic BA synthesis from cholesterol and induces expression of low‐density lipoprotein cholesterol (LDL‐C) receptors on hepatocytes 13. Thus, elobixibat decreases the plasma LDL‐C level.…”