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    Deletion of LDLRAP1 Induces Atherosclerotic Plaque Formation, Insulin Resistance, and Dysregulated Insulin Response in Adipose Tissue

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    Genre
    Thesis/Dissertation
    Date
    2022
    Author
    Leigh, Tani cc
    Advisor
    Autieri, Michael V.
    Committee member
    Scalia, Rosario
    Yu, Jun
    Rizzo, Victor
    Kilpatrick, Laurie
    Bellas, Evangelia
    Department
    Biomedical Sciences
    Subject
    Physiology
    Adipose pathophysiology
    Cardiovascular disease
    Insulin resistance
    Metabolic syndrome
    Vascular pathophysiology
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/8023
    
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    DOI
    http://dx.doi.org/10.34944/dspace/7995
    Abstract
    Atherosclerosis and symptoms of metabolic syndrome such as obesity, high cholesterol, and insulin resistance often coincide and exacerbate one another, but the cellular and molecular events in common with these conditions have not yet been fully elucidated. Low density lipoprotein receptor adaptor protein 1 (LDLRAP1) is an adaptor protein which interacts with the cytoplasmic tail of the LDL receptor, internalizing the receptor when it engages with LDL. Mutations in this gene lead to LDLR malfunction and cause Autosomal Recessive Hypercholesterolemia (ARH) in humans; however, direct causality on atherogenesis or metabolism in a defined pre-clinical model has not been reported. The aim of this study was to test the hypothesis that deletion of LDLRAP1 would lead to hypercholesterolemia and atherosclerosis. LDLRAP1-/- mice fed a high fat, western diet (HFD) for 16 weeks had significantly increased plasma cholesterol and triglyceride concentrations, accompanied with significantly increased plaque burden compared with wild-type controls. Unexpectedly, LDLRAP1-/- mice gained significantly more weight compared to the wild-type, LDLRAP1-/- mice were insulin resistant, and calorimetric studies suggested an altered metabolic profile. We determined that LDLRAP1 is highly expressed in white adipose tissue (WAT), and LDLRAP1-/- adipocytes are significantly larger and have reduced glucose uptake and AKT phosphorylation, but increased CD36 expression. WAT from LDLRAP1-/- mice is hypoxic, and has gene expression signatures of dysregulated lipid storage and energy homeostasis. These data indicate that lack of LDLRAP1 directly leads to atherosclerosis in mice, and also are the first to suggest that LDLRAP1 plays an unanticipated metabolic regulatory role in adipose tissue. LDLRAP1 deletion leads to systemic effects, and may act as a molecular link which regulates dyslipidemia, atherosclerosis, insulin resistance, and obesity.
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