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Publication
Low-density lipoprotein receptor-related protein 1 (LRP1) is a novel receptor
for apolipoprotein A4 (APOA4) in adipose tissue.
Authors Qu J, Fourman S, Fitzgerald M, Liu M, Nair S, Oses-Prieto J, Burlingame A,
Morris JH, Davidson WS, Tso P, Bhargava A
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal Scientific reports
Year 2021
Date Published 6/1/2021
Volume : Pages 11 : 13289
PubMed Reference 34168225
Abstract Apolipoprotein A4 (APOA4) is one of the most abundant and versatile
apolipoproteins facilitating lipid transport and metabolism. APOA4 is
synthesized in the small intestine, packaged onto chylomicrons, secreted into
intestinal lymph and transported via circulation to several tissues, including
adipose. Since its discovery nearly 4 decades ago, to date, only platelet
integrin aIIbß3 has been identified as APOA4 receptor in the plasma. Using
co-immunoprecipitation coupled with mass spectrometry, we probed the APOA4
interactome in mouse gonadal fat tissue, where ApoA4 gene is not transcribed but
APOA4 protein is abundant. We demonstrate that lipoprotein receptor-related
protein 1 (LRP1) is the cognate receptor for APOA4 in adipose tissue. LRP1
colocalized with APOA4 in adipocytes; it interacted with APOA4 under fasting
condition and their interaction was enhanced during lipid feeding concomitant
with increased APOA4 levels in plasma. In 3T3-L1 mature adipocytes, APOA4
promoted glucose uptake both in absence and presence of insulin in a
dose-dependent manner. Knockdown of LRP1 abrogated APOA4-induced glucose uptake
as well as activation of phosphatidylinositol 3 kinase (PI3K)-mediated protein
kinase B (AKT). Taken together, we identified LRP1 as a novel receptor for APOA4
in promoting glucose uptake. Considering both APOA4 and LRP1 are multifunctional
players in lipid and glucose metabolism, our finding opens up a door to better
understand the molecular mechanisms along APOA4-LRP1 axis, whose dysregulation
leads to obesity, cardiovascular disease, and diabetes.




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