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

Ivo P van de Peppel, Anna Bertolini, Theo H van Dijk, Albert K Groen, Johan W Jonker*, Henkjan J Verkade

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

20 Citations (Scopus)
309 Downloads (Pure)

Abstract

Transintestinal cholesterol excretion (TICE) is a major route for eliminating cholesterol from the body and a potential therapeutic target for hypercholesterolemia. The underlying mechanism, however, is largely unclear, and its contribution to cholesterol disposal from the body is obscured by the counteracting process of intestinal cholesterol reabsorption. To determine the quantity of TICE independent from its reabsorption, we studied two models of decreased intestinal cholesterol absorption. Cholesterol absorption was inhibited either by ezetimibe or, indirectly, by the genetic inactivation of the intestinal apical sodium-dependent bile acid transporter (ASBT; SLC10A2). Both ezetimibe treatment and Asbt inactivation virtually abrogated fractional cholesterol absorption (from 46% to 4% and 6%, respectively). In both models, fecal neutral sterol excretion and net intestinal cholesterol balance were considerably higher than in control mice (5- and 7-fold, respectively), suggesting that, under physiological conditions, TICE is largely reabsorbed. In addition, the net intestinal cholesterol balance was increased to a similar extent but was not further increased when the models were combined, suggesting that the effect on cholesterol reabsorption was already maximal under either condition alone. On the basis of these findings, we hypothesize that the inhibition of cholesterol (re)absorption combined with stimulating TICE will be most effective in increasing cholesterol disposal.

Original languageEnglish
Pages (from-to)1562-1572
Number of pages11
JournalJournal of Lipid Research
Volume60
Issue number9
Early online date19-Jul-2019
DOIs
Publication statusPublished - Sept-2019

Keywords

  • ASBT inhibition
  • intestinal cholesterol absorption
  • transintestinal cholesterol excretion
  • ezetimibe
  • BILE-ACID TRANSPORT
  • LIVER-X-RECEPTOR
  • NEUTRAL STEROL EXCRETION
  • REDUCES ATHEROSCLEROSIS
  • PLASMA-CHOLESTEROL
  • EZETIMIBE
  • ABSORPTION
  • METABOLISM
  • INHIBITION
  • MICE

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