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

Abstract

Dyslipidemia, vascular inflammation, obesity, and insulin resistance often overlap and exacerbate each other. Mutations in low density lipoprotein receptor adaptor protein-1 (LDLRAP1) lead to LDLR malfunction and are associated with the autosomal recessive hypercholesterolemia disorder in humans. However, direct causality on atherogenesis in a defined preclinical model has not been reported. The objective of this study was to test the hypothesis that deletion of LDLRAP1 will lead to hypercholesteremia and atherosclerosis. LDLRAP1^-/- mice fed a high-fat Western diet 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 with controls. Even on a chow diet, LDLRAP1^-/- mice were insulin-resistant, and calorimetric studies suggested an altered metabolic profile. The study showed that LDLRAP1 is highly expressed in visceral adipose tissue, and LDLRAP1^-/- adipocytes are significantly larger, have reduced glucose uptake and AKT phosphorylation, but have increased CD36 expression. Visceral adipose tissue from LDLRAP1^-/- mice was hypoxic and had gene expression signatures of dysregulated lipid storage and energy homeostasis. These data are the first to indicate that lack of LDLRAP1 directly leads to atherosclerosis in mice and also plays an unanticipated metabolic regulatory role in adipose tissue. LDLRAP1 may link atherosclerosis and hypercholesterolemia with common comorbidities of obesity and insulin resistance.