Le gène codant pour l’I-BABP est-il impliqué dans l’homéostasie du cholestérol ?

Abstract

La réabsorption intestinale des acides biliaires joue un rôle prépondérant dans le maintien de l’homéostasie du cholestérol. En effet, la perte fécale des acides biliaires constitue une importante voie d’élimination physiologique du cholestérol. L’I-BABP (ileal bile acid-binding protein) est un polypeptide soluble largement exprimé dans les cellules absorbantes de l’intestin grêle distal, connues pour être le siège d’une réabsorption active extrêmement efficace des acides biliaires. Des résultats récents démontrent que l’expression du gène codant pour l’I-BABP est profondément influencée par les concentrations d’acides biliaires et de cholestérol. Cette régulation requiert l’intervention de facteurs de transcription (FXR, LXR, SREBP) dont on sait qu’ils jouent un rôle homéostatique crucial dans le métabolisme lipidique, en général, et dans celui du cholestérol, en particulier. Ces observations inédites suggèrent que l’expression du gène de l’I-BABP intervient dans le devenir des acides biliaires et du cholestérol à l’échelle de l’organisme.

In the body, cholesterol balance results from an equilibrium between supplies (diet and cellular de novo synthesis), and losses (cellular use and elimination in feces, essentially as bile acids). Bile acids are synthesized from cholesterol in the liver. After conjugation to glycine or taurine, bile acids are secreted with bile in the intestinal lumen where they actively participate to the digestion and absorption of dietary fat and lipid-soluble vitamins. In healthy subjects, more than 95 % of bile acids are reabsorbed throughout the small intestine and returned by the portal vein to the liver, where they are secreted again into bile. This enterohepatic circulation is essential for maintenance of bile acids balance, and hence, for cholesterol homeostasis. Indeed, the bile acids not reclaimed by intestinal absorption constitute the main physiological way to eliminate a cholesterol excess. Little is known about the molecular mechanisms controlling bile acids reabsorption by the small intestine. The intestinal bile acids uptake mainly takes place through an active transport located in the distal part of the small intestine. To date, four unrelated proteins exhibiting a high affinity for bile acids have been identified in the ileum, and only one, the ileal bile acid-binding protein (I-BABP) is a soluble protein. Therefore, it is thought to be essential for efficient bile acids desorption from the apical plasma membrane, as well as for bile acids intracellular trafficking and targeting towards the basolateral membrane. If this assumption is correct, the I-BABP expression level might be rate limiting for the enterohepatic bile acids circulation, and hence, for cholesterol homeostasis. It was found that both bile acids and cholesterol, probably via oxysterols, are able to up-regulate the trancription rate of I-BABP gene. The fact that intracellular sterol sensors (FXR, LXR, and SREBP1c) are involved in the control of the I-BABP gene expression strongly suggests that I-BABP exerts an important role in maintenance of cholesterol balance.