TY - JOUR
T1 - Deletion of LDLRAP1 Induces Atherosclerotic Plaque Formation, Insulin Resistance, and Dysregulated Insulin Response in Adipose Tissue
AU - Leigh, Tani
AU - Kawai, Tatsuo
AU - Preston, Kyle
AU - Kelemen, Sheri
AU - Okune, Rachael
AU - St Paul, Amanda
AU - Corbett, Cali
AU - Peluzzo, Amanda M.
AU - Yu, Jun
AU - Scalia, Rosario G.
AU - Autieri, Michael V.
N1 - Copyright © 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
PY - 2022/7
Y1 - 2022/7
N2 - 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.
AB - 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.
KW - Adipose Tissue/metabolism
KW - Animals
KW - Atherosclerosis/etiology
KW - Diet, High-Fat/adverse effects
KW - Hyperlipidemias/complications
KW - Insulin Resistance
KW - Insulin/metabolism
KW - Mice
KW - Mice, Knockout
KW - Obesity/complications
KW - Plaque, Atherosclerotic/genetics
KW - Receptors, LDL/genetics
UR - http://www.scopus.com/inward/record.url?scp=85132756299&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000833423400004&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1016/j.ajpath.2022.03.014
DO - 10.1016/j.ajpath.2022.03.014
M3 - Article
C2 - 35460615
SN - 0002-9440
VL - 192
SP - 1092
EP - 1108
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 7
ER -