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Principal Investigator: Hasan Zaki
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $524,056
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <Anabolism><Animal Model><Animal Models and Related Studies><Arterial Fatty Streak><Arterial Fatty Streaks><Assay><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Bioassay><Biochemical><Biological><Biological Assay><Biological Function><Biological Process><Blood><Blood Reticuloendothelial System><Body Tissues><CD36><CD36 gene><Cardiovascular Diseases><Causality><Cell Communication and Signaling><Cell Signaling><Cell surface><Chemical Injury><Cholesterol><Chronic><Clinical Markers><Colitis><Critical Paths><Critical Pathways><DSS colitis><DSS model><DSS mouse model><DSS-induced acute colitis><DSS-induced colitis><Data><Deposit><Deposition><Diabetes Mellitus><Diathesis><Disease><Disease susceptibility><Disorder><Drug usage><Dysfunction><Dyslipidemias><Endocytosis><Endosomes><Etiology><Event><Extracellular Signal-Regulated Kinase Gene><Functional disorder><GI microbiota><GP3B><GP4><GPIV><Gastrointestinal microbiota><Genetic Models><Goals><HDL><HDL Lipoproteins><Heavy Lipoproteins><High Density Lipoproteins><High Fat Diet><High density lipoprotein><Immune signaling><Immunoglobulin Enhancer-Binding Protein><In Vitro><Inflammation><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Inflammatory Response><Intake><Intermediary Metabolism><Intestinal><Intestines><Intracellular Communication and Signaling><Knowledge><LDL><LDL Cholesterol><LDL Cholesterol Lipoproteins><LDL Lipoproteins><LDL Receptors><Link><Lipids><Lipoprotein LDL Receptors><Lipoproteins><Low Density Lipoprotein Cholesterol><Low Density Lipoprotein Receptor><Low-Density Lipoproteins><MAP Kinase Gene><MAPK><Macromolecular Structure><Macrophage><Measures><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolic syndrome><Metabolism><Mice><Mice Mammals><Mitogen-Activated Protein Kinase Gene><Modeling><Modification><Molecular Biology Techniques><Molecular Structure><Murine><Mus><Myeloid Cells><Mφ><NF-kB><NF-kappa B><NF-kappaB><NFKB><Names><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Obesity><OxLDL><Pathogenesis><Pathogenicity><Pathologic><Pathway interactions><Peripheral><Physiologic><Physiological><Physiology><Physiopathology><Play><Predisposition><Receptor Protein><Receptor-Interacting Protein><Receptosomes><Research><Risk Factors><Role><SCARB3><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Susceptibility><Testing><Thesaurismosis><Time><Tissues><Transcription Factor NF-kB><adiposity><alpha-Lipoproteins><atheromatosis><atherosclerosis plaque><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><beta-Lipoprotein Cholesterol><beta-Lipoproteins><biologic><biological signal transduction><biosynthesis><bowel><bowel inflammation><cardiovascular disorder><causation><cell type><chemical trauma><colitis mouse model><colitis murine model><colitis-induced dysbiosis><corpulence><dextran sulfate sodium colitis><dextran sulfate sodium induced colitis><dextran sulfate sodium model><dextran sulfate sodium mouse model><diabetes><disease causation><drug use><enteric microbial community><enteric microbiota><gastrointestinal microbial flora><gut commensal><gut community><gut flora><gut inflammation><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiota><gut microbiotic><gut microflora><human disease><in vivo><inflamed bowel><inflamed gut><inflamed intestine><inflammatory disease of the intestine><inflammatory disorder of the intestine><innate immune pathways><innovate><innovation><innovative><intestinal autoinflammation><intestinal flora><intestinal inflammation><intestinal microbiota><intestinal microflora><intestinal tract microflora><kappa B Enhancer Binding Protein><liability to disease><metabolism disorder><model of animal><mouse colitis><murine colitis><name><named><naming><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><nuclear factor kappa beta><ox-LDL><oxidized LDL><oxidized low density lipoprotein><pathophysiology><pathway><receptor><receptor mediated endocytosis><social role><stem><vulnerable plaque><western diet><western-style diet><western-type diet>