ISX is a retinoic acid‐sensitive gatekeeper that controls intestinal β,β‐carotene absorption and vitamin A production

Abstract

The uptake of dietary lipids from the small intestine is a complex process that depends on the activities of specific membrane receptors with yet unknown regulatory mechanisms. Using both mouse models and human cell lines, we show here that intestinal lipid absorption by the scavenger receptor class B type 1 (SR-BI) is subject to control by retinoid signaling. Retinoic acid via retinoic acid receptors induced expression of the intestinal transcription factor ISX. ISX then repressed the expression of SR-B1 and the carotenoid-15,15'-oxygenase Bcmo1. BCMO1 acts downstream of SR-BI and converts absorbed beta,beta-carotene to the retinoic acid precursor, retinaldehyde. Using BCMO1-knockout mice, we demonstrated increased intestinal SR-BI expression and systemic beta,beta-carotene accumulation. SR-BI-dependent accumulation of beta,beta-carotene was prevented by dietary retinoids that induced ISX expression. Thus, our study revealed a diet-responsive regulatory network that controls beta,beta-carotene absorption and vitamin A production by negative feedback regulation. The role of SR-BI in the intestinal absorption of other dietary lipids, including cholesterol, fatty acids, and tocopherols, implicates retinoid signaling in the regulation of lipid absorption more generally and has clinical implications for diseases associated with dyslipidemia.

BCDO2 acts as a carotenoid scavenger and gatekeeper for the mitochondrial apoptotic pathway

“…intestinal carotenoid absorption is greatly attenuated by dietary retinoids (Lobo et al, 2010b). This characteristic explains why Bcdo2 deficiency does not result in similar effects during mouse embryogenesis .…”

“…Rodents such as mice display low to undetectable levels of these compounds in blood and tissues (Hessel et al, 2007;Amengual et al, 2011), indicating that they have developed mechanisms to prevent carotenoid accumulation. Indeed, recent research revealed that intestinal carotenoid absorption is under negative-feedback regulation by vitamin A (Lobo et al, 2010b) and that non-proretinoid carotenoids are rapidly metabolized by BCDO2 (Ford et al, 2010;Amengual et al, 2011). By contrast, many mammals, including humans, and oviparous vertebrates, such as birds and fish, have significant levels of carotenoids in blood and tissues.…”

Vitamin A supplementation in early life affects later response to an obesogenic diet in rats

“…ISX is a gut-specific transcription factor that is induced in intestinal cells by RA via RAR and functions to limit intestinal beta-carotene absorption and conversion to vitamin A through its effects on gene expression. 43 CYP26a1 is a RA hydroxylase that is transcriptionally induced by RA in a RAR-dependent manner. 44 ISX mRNA levels in intestine and CYP26a1 mRNA levels in liver and iWAT were higher in the RE rats than in the control rats (Figures 2a-c), indicating increased RA-mediated transcriptional responses in tissues of RE-treated animals.…”

Effects of Mixed Micellar Lipids on Carotenoid Uptake by Human Intestinal Caco-2 Cells

“…[17][18][19][20][21][22][23][24] Scavenger receptor class B type 1 (SR-B1) might be a major receptor in the facilitated diffusion in Caco-2 cells, considering the results of studies using their antibodies and siRNAs. 22,25) In SR-B1 knockout mice, the efficiency of -carotene absorption was remarkably reduced, though not fully inhibited.…”