Regulation of intestinal lipid synthesis, apolipoprotein biogenesis and lipoprotein assembly by retinoic acid

Abstract

Retinoids are involved in a wide range of biological processes, including cell proliferation, differentiation and morphogenesis. Their deficiency can adversely affect health, as evidenced by various clinical signs. Even if retinoids play a critical role in a variety of essential life processes, their regulatory effects on intestinal lipid transport remain obscure. Since significant advances have documented the ability of retinoids to arrest or reverse the process of carcinogenesis, we hypothesize that retinoic acid (RA) is able to modulate intestinal cell differentiation and function, including HDL formation. Our results revealed that RA was more active in inhibiting proliferation and inducing differentiation of Caco-2 cells in culture. Evidence was also presented to suggest that phosphatidylinositol-3 kinase (PI3K) was increased, which subsequently enhanced the expression of enterocyte markers, cell polarization and brush-border formation. Furthermore, the addition of RA to Caco-2 cells for 4h in the presence of [35S]-methionine substantially elicited apolipoprotein (apo) A-I biogenesis, reflecting an augmentation of HDL particles. However, the incubation of Caco-2 cells for longer periods (12–24h) with RA did not result in raised levels of lipid esterification (triglycerides, phospholipids, cholesteryl esters), apo synthesis (A-I, A-IV, B-48) and lipoprotein packaging (chylomicron, VLDL, LDL, HDL). Overall, our findings propose that RA regulates intestinal cell differentiation and stress the rapid apo A-I production, probably via the induction of nuclear receptors, such as RAR and RXR.