Novel Function of Native Low-Density Lipoprotein in Inflammation

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SUMMARY Lipid and cholesterol-rich Western diet is a major risk factor for many non-communicable diseases, including cardiovascular disease, obesity, diabetes, metabolic syndrome, and inflammatory bowel disease (IBD). A common lipid derivative associated with the pathogenesis of these inflammatory and metabolic diseases is low-density lipoprotein (LDL) which is scavenged by its receptor (LDLR) expressed in almost all tissue. Despite the known function of LDL in atherosclerosis, its role in other diseases is poorly understood. Inflammation is a common trigger for atherosclerosis and other non-communicable diseases. However, whether native LDL, which is the most abundant physiological form of LDL, is involved in the inflammatory response is unknown. The goal of this study is to define a role of native LDL in inflammatory response, so the association of LDL with many human diseases can be explained. This critically important objective was stemmed from our preliminary studies in which we observed that mice having high blood LDL are highly susceptible to experimental colitis. Interestingly, mice defective in LDLR (Ldlr-/-) were relatively protective against colitis. Reduced colitis susceptibility of Ldlr-/- mice was associated with suppressed inflammation and decreased activation of inflammatory signaling pathways such as NF- kB and MAPK, pointing to an uncharacterized function of LDL/LDLR in inflammation. Indeed, we observed that native LDL stimulates macrophages in vitro to produce inflammatory molecules. Given that no study yet documented a role of native LDL in innate immune signaling and inflammatory responses, our observation underscored a novel mechanism of pathogenesis of inflammatory disorders associated with high blood LDL. We, therefore, hypothesize that endocytosis of LDL through LDLR induces inflammatory responses in myeloid cells causing inflammation, and such an inflammatory pathway imparts a major contribution in inflammatory disorders like colitis. This hypothesis will be tested through two specific aims: Aim 1. To dissect the pathway involved in LDL-mediated induction of inflammatory responses; Aim 2. To define the role of native LDL and its receptor in intestinal inflammation. Using biochemical and molecular biology techniques, we will explore signaling events and mechanisms involved in LDL/LDLR-mediated activation of NF-B and MAPK pathways. We will use Ldlr-/- mice and mouse models of colitis to investigate the in vivo relevance of LDL/LDLR in inflammatory disorders. Overall, this study will explore a novel biological function of native LDL which will help elucidate the pathogenic mechanism of diseases associated with high blood LDL. Furthermore, this study will decipher a yet unknown role of blood LDL in colitis pathogenesis. The findings of this study will open the opportunity to treat IBD and other non- communicable diseases by targeting LDL synthesis or LDLR downstream signaling pathways.