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

Abstract

Recent studies have indicated that direct intestinal secretion of plasma cholesterol significantly contributes to fecal neutral sterol loss in mice. The physiological relevance of this novel route, which represents a part of the reverse cholesterol transport pathway, has not been directly established in vivo as yet. We have developed a method to quantify the fractional and absolute contributions of several cholesterol fluxes to total fecal neutral sterol loss in vivo in mice, by assessing the kinetics of orally and intravenously administered stable isotopically labeled cholesterol combined with an isotopic approach to assess the fate of de novo synthesized cholesterol. Our results show that trans-intestinal cholesterol excretion significantly contributes to removal of blood-derived free cholesterol in C57Bl6/J mice (33% of 231 mol/kg/day) and that pharmacological activation of LXR with T0901317 strongly stimulates this pathway (63% of 706 mol/ kg/day). Trans-intestinal cholesterol excretion is impaired in mice lacking Abcg5 (؊4%), suggesting that the cholesterol transporting Abcg5/Abcg8 heterodimer is involved in this pathway. Our data demonstrate that intestinal excretion represents a quantitatively important route for fecal removal of neutral sterols independent of biliary secretion in mice. This pathway is sensitive to pharmacological activation of the LXR system. These data support the concept that the intestine substantially contributes to reverse cholesterol transport. Reverse cholesterol transport (RCT)3 is defined as the flux of excess cholesterol from peripheral tissues toward the liver followed by biliary secretion and subsequent disposal via the feces (1). Accumulation of cholesterol in macrophages in the vessel wall is considered a primary event in the development of atherosclerosis and, therefore, removal of excess cholesterol from these cells is of crucial importance for prevention and/or treatment of atherosclerotic cardiovascular diseases. It is generally accepted that HDL is the obligate transport vehicle in RCT and that plasma HDL levels reflect the capacity to accommodate this flux. In line herewith, HDL-raising therapies are currently considered as a promising strategy for prevention and treatment of atherosclerotic cardiovascular diseases (2). In the "classical" scenario, the liver has a central role in RCT (3). Biliary secretion of free cholesterol, facilitated by the heterodimeric ABC-transporter ABCG5/ABCG8 (4), and hepatic conversion of cholesterol into bile acids followed by fecal excretion are referred to as the main routes for quantitatively important elimination of cholesterol from the body. Fecal excretion of sterols is stimulated upon whole body activation of the liver X receptor (LXR, NR1H2/3), a member of the nuclear receptor family for which oxysterols have been identified as natural ligands (5). LXR regulates expression of several genes involved in RCT and activation of LXR by synthetic agonists leads to elevated plasma HDL-cholesterol levels, increased hepatobiliary cholestero...

Insig Proteins Mediate Feedback Inhibition of Cholesterol Synthesis in the Intestine

“…Preliminary data suggest that fecal cholesterol contents of Vil-Insig ؊ mice seem to be slightly higher than that of control mice under chow-fed conditions. Future quantitative whole-body cholesterol balance studies, such as the method developed by van der Vee et al (39), will be necessary to elucidate the potential alterations of TICE in VilInsig ؊ mice. The effect of increasing intestinal cholesterol synthesis on the liver is reminiscent of the effect of feeding cholesterol-rich diets.…”

L’excrétiontrans-intestinale de cholestérol (TICE)

“…Enfin, ce même groupe a démontré que le TICE est principalement actif dans la partie proximale de l'intestin ; les auteurs ont estimé que, chez des souris C57BL6, 33 % du cholestérol fécal proviendraient du TICE, alors que 17 % proviendraient de la voie biliaire. Ces résultats font du TICE une voie majeure d'épuration du cholestérol de l'organisme [9]. Cependant, la contribution relative cette voie à l'excrétion fécale de cholestérol est probablement dépendante du fonds génétique de la souris étudiée ; chez les souris FVB (Friend virus B-type), la contribution du TICE serait de 20 % [6].…”

“…Plösch et al ont montré que l'activation des récepteurs nucléaires LXR (liver X receptor) augmente l'excrétion fécale de cholestérol de façon similaire chez les souris sauvages et les souris invalidées pour le transporteur ABCA1, chez lesquelles on observe une quasi absence de HDL circulants [12]. De même, les agonistes LXR, des stimulateurs reconnus du TICE (voir plus loin [6,9]), réduisent dans les mêmes conditions expérimentales l'accumulation intestinale d'éther de cholestérol (cholestérol non métabolisable) provenant d'HDL, faisant douter de l'importance fonctionnelle des HDL dans le TICE [13]. Deux études récentes ont mesuré de façon directe le TICE après une injection intraveineuse d'HDL marqués au cholestérol radioactif.…”

Regulation of Intestinal Cholesterol Absorption: A Disease Perspective

“…Around 20% -33% of basal fecal sterol loss has been estimated due to TICE in both human [56] and mice [57]. It has been shown that the non-biliary TICE pathway can be stimulated by activation of LXR [57] and PPARδ [58], ezetimibe administration [59], and fasting [60]. However, the precise underlying mechanisms and pathways for the induction of TICE are still unknown.…”

“…Although TICE can occur throughout the small intestine, but most of the TICE happens in the proximal intestine [55]. Around 20% -33% of basal fecal sterol loss has been estimated due to TICE in both human [56] and mice [57]. It has been shown that the non-biliary TICE pathway can be stimulated by activation of LXR [57] and PPARδ [58], ezetimibe administration [59], and fasting [60].…”