Increased Intestinal Lipid Absorption Caused by Ire1β Deficiency Contributes to Hyperlipidemia and Atherosclerosis in Apolipoprotein E-Deficient Mice

Rationale: High fasting serum lipid levels are significant risk factors for atherosclerosis. However, the contributions of postprandial excursions in serum lipoproteins to atherogenesis are less well-characterized. Objective: This study aims to delineate whether changes in intestinal lipid absorption associated with loss of inositol-requiring enzyme 1 beta (Ire1 beta) would affect the development of hyperlipidemia and atherosclerosis in Apoe(-/-) mice. Methods and Results: We used Ire1 beta-deficient mice to assess the contribution of intestinal lipid absorption to atherosclerosis. Here, we show that Ire1b(-/-)/Apoe(-/-) mice contain higher levels of intestinal microsomal triglyceride transfer protein, absorb more lipids, exhibit hyperlipidemia, and have higher levels of atherosclerotic plaques compared with Apoe(-/-) mice when fed chow and western diets. Conclusions: These studies indicate that Ire1 beta regulates intestinal lipid absorption and that increased intestinal lipoprotein production contributes to atherosclerosis. (Circ Res. 2012;110:1575-1584.)