Low-density lipoprotein receptor-related protein 1 (LRP1) is a novel receptor for apolipoprotein A4 (APOA4) in adipose tissue

Jie Qu,Sarah Fourman,Aditi Bhargava,Maureen Fitzgerald,Juan Oses-Prieto,Alma Burlingame,Min Liu,Patrick Tso,W Sean Davidson,Supna Nair,John H Morris

doi:10.1038/s41598-021-92711-0

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 αIIbβ3 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.

Highlights

Metabolic syndrome, a cluster of conditions that increase the risks of obesity and type 2 diabetes, together with cardiovascular diseases has reached epidemic proportions worldwide in the past decade[1]
We reasoned that Apolipoprotein A4 (APOA4) protein synthesized in the gut and/or the liver is transported via circulation to target organs that do not normally transcribe ApoA4 mRNA
Immunostaining and confocal microscopy confirmed the presence of immunoreactive APOA4 in gonadal adipose tissues from both sexes of WT mice, where it localized to the cell surface and in the vasculature (Fig. 1C, arrow and inset: arrowhead, respectively), but no immunoreactivity was detected in gonadal adipose tissue of ApoA4−/− mice (Fig. 1D)

Summary

Introduction

A cluster of conditions that increase the risks of obesity and type 2 diabetes, together with cardiovascular diseases has reached epidemic proportions worldwide in the past decade[1]. The human apolipoprotein (APO) A4 gene is located in the APOA1/C3/A4/A5 gene cluster on chromosome 11q23 and the mouse ApoA4 gene is on chromosome 9 This gene cluster is essential for lipoprotein metabolism, lipid homeostasis and susceptibility to cardiovascular diseases[5,6,7]. LRP1 plays prominent role in lipid homeostasis by mediating the clearance of ApoE-enriched chylomicron and very low-density lipoprotein r emnants[36] and by interacting with hepatic lipase and lipoprotein lipase[37]. LRP1 is important for glucose metabolism by suppressing gluconeogenesis and protecting against hepatic insulin resistance[38] In adipose tissue, it regulates postprandial lipid clearance, glucose metabolism and energy homeostasis[39]. The membrane proteins interacting with APOA4 remain largely unknown

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