Microsomal Triglyceride Transfer Protein Regulated by NR2F1 and IRE1β Determines Chylomicron Production

Abstract

Microsomal triglyceride transfer protein (MTP) and apolipoprotein B (apoB) are essential for the assembly and secretion of apoB-containing lipoproteins. In the small intestine, only enterocytes produce lipoproteins, called as chylomicron (CM). Enterocytes are arising from intestinal stem/progenitor cells through a process called differentiation. It is unknown how these enterocytes gain lipid absorption property during differentiation. In this thesis, Caco-2 cells, human colon adenocarcinoma that have intrinsic property to differentiate into enterocyte-like epithelia in culture, were used to identify genes that regulate the assembly and secretion of apoB-lipoproteins and lipid absorption. My studies indicate that MTP is a limiting factor for apoB-lipoprotein assembly and secretion by undifferentiated cells. Increased expression of MTP propels the production of apoB-lipoproteins during differentiation. Further studies reveal that a putative repressor, nuclear receptor family 2 group F member 1 (NR2F1), and an endoplasmic reticulum stress protein, inositol-requiring enzyme 1β (IRE1β), inhibit MTP expression in undifferentiated cells involving transcriptional and posttranscriptional mechanisms, respectively. Decreased expression of NR2F1 and IRE1β during differentiation allows differentiation-dependent induction of MTP ensuing CM production. Studying the expression of MTP, NR2F1 and IRE1β, in the mouse intestine indicates that the mechanisms unveiled in Caco-2 cell might be operative in vivo. Furthermore, IRE1β-null mice express more intestinal MTP and absorb more dietary lipids when fed high fat or high cholesterol diets, confirming that IRE1β negatively regulates intestinal MTP expression. Identification of these two new regulatory genes might be insightful for developing novel methods to lower intestinal MTP activity and plasma lipid level.