IRE1β inhibits chylomicron production by selectively degrading MTP mRNA

Microsomal triglyceride transfer protein (MTP) is needed to assemble chylomicrons in the endoplasmic reticulum (ER) of enterocytes. We explored the role of an ER stress protein, inositol-requiring enzyme 1 beta (IRE1 beta), in regulating this process. High-cholesterol and high-fat diets decreased intestinal IRE1 beta mRNA in wild-type mice. Ire1b(-/-) mice fed high-cholesterol and high-fat diets developed more pronounced hyperlipidemia because these mice secreted more chylomicrons and expressed more intestinal MTP, though not hepatic MTP, than wildtype mice did. Chylomicron secretion and MTP expression also were increased in primary enterocytes isolated from cholesterol-fed Ireb(-/-) mice. There was no correlation between ER stress and MTP expression. Instead, cell culture studies revealed that IRE1 beta, but not its ubiquitous homolog IRE1 alpha, decreased MTP mRNA through increased posttranscriptional degradation. Conversely, knockdown of IRE1 beta enhanced MTP expression. These studies show that IRE1 beta plays a role in regulating MTP and in chylomicron production.