Effect of chronic intermittent hypoxia on triglyceride uptake in different tissues

Qiaoling Yao,Mi-Kyung Shin,Jonathan C Jun,Karen L Hernandez,Neil R Aggarwal,Jason R Mock,Jason Gay,Luciano F Drager,Vsevolod Y Polotsky

doi:10.1194/jlr.m034272

Abstract

Chronic intermittent hypoxia (CIH) inhibits plasma lipoprotein clearance and adipose lipoprotein lipase (LPL) activity in association with upregulation of an LPL inhibitor angiopoietin-like protein 4 (Angptl4). We hypothesize that CIH inhibits triglyceride (TG) uptake via Angptl4 and that an anti-Angptl4-neutralizing antibody would abolish the effects of CIH. Male C57BL/6J mice were exposed to four weeks of CIH or intermittent air (IA) while treated with Ab (30 mg/kg ip once a week). TG clearance was assessed by [H(3)]triolein administration retroorbitally. CIH delayed TG clearance and suppressed TG uptake and LPL activity in all white adipose tissue depots, brown adipose tissue, and lungs, whereas heart, liver, and spleen were not affected. CD146+ CD11b- pulmonary microvascular endothelial cells were responsible for TG uptake in the lungs and its inhibition by CIH. Antibody to Angptl4 decreased plasma TG levels and increased TG clearance and uptake into adipose tissue and lungs in both control and CIH mice to a similar extent, but did not reverse the effects of CIH. The antibody reversed the effects of CIH on LPL in adipose tissue and lungs. In conclusion, CIH inactivates LPL by upregulating Angptl4, but inhibition of TG uptake occurs predominantly via an Angptl4/LPL-independent mechanism.

Highlights

Chronic intermittent hypoxia (CIH) inhibits plasma lipoprotein clearance and adipose lipoprotein lipase (LPL) activity in association with upregulation of an LPL inhibitor angiopoietin-like protein 4 (Angptl4)
We have recently shown that CIH impairs chylomicron clearance in mice and inhibits a key enzyme of triglyceride-rich lipoprotein clearance, lipoprotein lipase (LPL), in adipose tissue [24]
Mice exposed to intermittent air (IA) were weight-matched to the CIH group and, there was no difference in body weight or food intake between the groups

Summary

Introduction

Chronic intermittent hypoxia (CIH) inhibits plasma lipoprotein clearance and adipose lipoprotein lipase (LPL) activity in association with upregulation of an LPL inhibitor angiopoietin-like protein 4 (Angptl). Antibody to Angptl decreased plasma TG levels and increased TG clearance and uptake into adipose tissue and lungs in both control and CIH mice to a similar extent, but did not reverse the effects of CIH. We developed a mouse model of CIH, which mimics oxyhemoglobin desaturations in patients with OSA [21,22,23] Using this model, we have recently shown that CIH impairs chylomicron clearance in mice and inhibits a key enzyme of triglyceride-rich lipoprotein clearance, lipoprotein lipase (LPL), in adipose tissue [24]. We exposed C57BL/6J mice to CIH for four weeks while treating them with Angptl4-neutralizing antibodies (Ab) or placebo (vehicle solution) and examined plasma clearance and tissue uptake of [H3]triolein-Intralipid

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