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. / Biomedical Sciences
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/8023 |
| Date | January 2022 |
| Creators | Leigh, Tani, 0000-0003-4395-0834 |
| Contributors | Autieri, Michael V., Scalia, Rosario, Yu, Jun, Rizzo, Victor, Kilpatrick, Laurie, Bellas, Evangelia |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 101 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/7995, Theses and Dissertations |
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