Regulation of direct transintestinal cholesterol excretion in mice

Abstract

Biliary secretion is generally considered to be an obligate step in the pathway of excess cholesterol excretion from the body. We have recently shown that an alternative route exists. Direct transintestinal cholesterol efflux (TICE) contributes significantly to cholesterol removal in mice. Our aim was to investigate whether the activity of this novel pathway can be influenced by dietary factors. In addition, we studied the role of cholesterol acceptors at the luminal side of the enterocyte. Mice were fed a Western-type diet (0.25% wt/wt cholesterol; 16% wt/wt fat), a high-fat diet (no cholesterol; 24% wt/wt fat), or high-cholesterol diet (2% wt/wt), and TICE was measured by isolated intestinal perfusion. Bile salt-phospholipid mixtures served as cholesterol acceptor. Western-type and high-fat diet increased TICE by 50 and 100%, respectively. In contrast, the high-cholesterol diet did not influence TICE. Intestinal scavenger receptor class B type 1 (Sr-B1) mRNA and protein levels correlated with the rate of TICE. Unexpectedly, although confirming a role for Sr-B1, TICE was significantly increased in Sr-B1-deficient mice. Apart from the long-term effect of diets on TICE, acute effects by luminal cholesterol acceptors were also investigated. The phospholipid content of perfusate was the most important regulator of TICE; bile salt concentration or hydrophobicity of bile salts had little effect. In conclusion, TICE can be manipulated by dietary intervention. Specific dietary modifications might provide means to stimulate TICE and, thereby, to enhance total cholesterol turnover.

Activation of the Liver X Receptor Stimulates Trans-intestinal Excretion of Plasma Cholesterol

“…SR-BI is localized both at the apical and basolateral membrane along the entire length, but mostly in the proximal part, of the small intestine (36). However, recent studies by van der Velde et al (37) show no reduction of TICE in mice lacking SR-BI, suggesting that this transporter is not involved in trans-intestinal cholesterol excretion. Recently, Brown et al (13) confirmed the existence of a non-biliary route for fecal sterol loss in mice with a targeted deletion of hepatic ACAT2.…”

L’excrétiontrans-intestinale de cholestérol (TICE)

“…On [15] (voir plus loin), et ces régimes induisent également l'expression intestinale de SRBI [15]. Au vu de cette corrélation, les auteurs ont suggéré que SRBI pourrait être impliqué de façon active dans le TICE.…”

“…Au vu de cette corrélation, les auteurs ont suggéré que SRBI pourrait être impliqué de façon active dans le TICE. Néanmoins, chez des souris SRBI knocked-out (KO), le TICE est, soit non modifié [14], soit significativement augmenté [15]. De même, une surexpression intestinale de SRBI chez des souris présentant un défaut d'excrétion biliaire de cholestérol n'a pas d'effet notable sur l'excrétion fécale de cholestérol [16].…”

“…Van der Velde et al ont ainsi mis en évidence que la présence d'accepteurs du cholestérol dans la lumière intestinale le stimule fortement [8,15]. En effet, in vivo, le TICE est détectable, mais faible, en l'absence d'accepteurs du cholestérol, et plus de 80 % du cholestérol présent dans les perfusats intestinaux ont alors pour origine la seule desquamation entérocy-taire.…”

“…Ces molécules permettent la formation de micelles qui vont pouvoir solubiliser le cholestérol excrété par les cellules intestinales. De plus, chez la souris, il semble que le TICE soit peu sensible à la concentration des acides biliaires dans la lumière intestinale et au type d'acides présents [15]. Le statut nutritionnel influe également sur le TICE.…”