Chronic Intermittent Hypoxia Induces Atherosclerosis via Activation of Adipose Angiopoietin-like 4

Drager, Luciano F.; Yao, Qiaoling; Hernandez, Karen L.; Shin, Mi Kyung; Bevans‐Fonti, Shannon; Sussan, Thomas E.; Jun, Jonathan C.; Myers, Allen C.; Olivecrona, Gunilla; Schwartz, Alan R.; Halberg, Nils; Scherer, Philipp E.; Semenza, Gregg L.; Powell, David R.; Polotsky, Vsevolod Y.

doi:10.1164/rccm.201209-1688oc

Cited by 146 publications

(128 citation statements)

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“…Expression of Angptl4 is regulated by hypoxia inducible factor 1 (HIF-1) ( 52-57 ). We have recently shown that CIH-induced upregulation of Angptl4 in visceral fat is abolished by heterozygous deficiency of HIF-1 ␣ , whereas constitutive overexpression of HIF-1 ␣ increases Angptl4 levels ( 58 ). Although mechanisms of selective upregulation of Angptl4 in OM and EPI WAT and lungs are unknown, we hypothesize that differential regulation of HIF-1 ␣ in different organs may play a role.…”

Section: Cih and Angptl4mentioning

confidence: 86%

Effect of chronic intermittent hypoxia on triglyceride uptake in different tissues

Yao

Shin

Jun

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org signifi cant cardiovascular morbidity and mortality (2)(3)(4). Several lines of evidence demonstrated that OSA is associated with dyslipidemia and accelerated atherosclerosis ( 5-12 ). A randomized, placebo-controlled clinical trial of continuous positive airway pressure (CPAP) has shown that OSA treatment with CPAP markedly reduces postprandial hyperlipidemia ( 13 ). Postprandial hypertriglyceridemia may confer risk for myocardial infarction, isch emic heart disease, stroke, and death (14)(15)(16)(17)(18)(19)(20). Therefore, it is conceivable that postprandial hyperlipidemia contributes to the cardiovascular risk of OSA. The pathogenesis of postprandial hyperlipidemia in OSA is unknown.We developed a mouse model of CIH, which mimics oxyhemoglobin desaturations in patients with OSA ( 21-23 ). 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 ). CIH also upregulated a potent LPL inhibitor, adipose angiopoietin-like protein 4 (Angptl4) ( 24 ). However, the effect of CIH on triglyceride (TG) uptake by adipose tissue has not been explored; contribution of other organs and tissues to lipoprotein clearance during CIH is unknown. Finally, the role of Angptl4 in CIH-induced metabolic dysfunction has not been determined.We hypothesized that CIH impairs TG uptake by adipose tissue depots and other organs and tissues via Angptl4. 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 [H 3 ]triolein-Intralipid. 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 A...

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Section: Cih and Angptl4mentioning

confidence: 86%

Effect of chronic intermittent hypoxia on triglyceride uptake in different tissues

Yao

Shin

Jun

et al. 2013

Journal of Lipid Research

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“…Rodent models more convincingly demonstrate dyslipidaemia proportional to duration and severity of chronic intermittent hypoxia [9][10][11][17][18][19][20][21]. LI et al [19] found increased fasting serum lipids in lean C57BL/6J mice exposed to 4 weeks of severe chronic intermittent hypoxia (inspiratory oxygen fraction 5%); no change was observed with moderate chronic intermittent hypoxia (inspiratory oxygen fraction 10%) [19].…”

Section: Discussionmentioning

confidence: 99%

“…To compare results with recent data from animal models [9][10][11][17][18][19][20][21], we limited our sample to patients in the top quartile of percentage of time at SaO 2 ,90%. No differences in fasting lipid changes between positive airway pressure adherent patients and non-users were observed (table E7).…”

Section: Patients With the Most Severe Hypoxiamentioning

confidence: 99%

“…Animal models demonstrate dyslipidaemia proportional to chronic intermittent hypoxia severity and development of atherosclerotic lesions [9][10][11][17][18][19][20][21]. However, while studies in mice support a causal relationship between chronic intermittent hypoxia and dyslipidaemia, human studies evaluating the effects of OSA [3][4][5][6][7][8][9][10][11] and positive airway pressure treatment [8][9][10][11][12][13][14][15][16] on lipid levels are inconsistent.…”

Section: Introductionmentioning

confidence: 99%

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Obstructive sleep apnoea treatment and fasting lipids: a comparative effectiveness study

et al. 2014

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Obstructive sleep apnoea (OSA) is associated with cardiovascular disease. Dyslipidaemia has been implicated as a mechanism linking OSA with atherosclerosis, but no consistent associations with lipids exist for OSA or positive airway pressure treatment. We assessed the relationships between fasting lipid levels and obesity and OSA severity, and explored the impact of positive airway pressure treatment on 2-year fasting lipid level changes.Analyses included moderate-to-severe OSA patients from the Icelandic Sleep Apnoea Cohort. Fasting morning lipids were analysed in 613 untreated participants not on lipid-lowering medications at baseline. Patients were then initiated on positive airway pressure and followed for 2 years. Sub-classification using propensity score quintiles, which aimed to replicate covariate balance associated with randomised trials and, therefore, minimise selection bias and allow causal inference, was used to design the treatment group comparisons. 199 positive airway pressure adherent patients and 118 non-users were identified.At baseline, obesity was positively correlated with triglycerides and negatively correlated with total cholesterol, and low-density and high-density lipoprotein cholesterol. A small correlation was observed between the apnoea/hypopnoea index and high-density lipoprotein cholesterol. No effect of positive airway pressure adherence on 2-year fasting lipid changes was observed.Results do not support the concept of changes in fasting lipids as a primary mechanism for the increased risk of atherosclerotic cardiovascular disease in OSA. @ERSpublications Fasting lipid changes are unaffected by positive airway pressure and thus don't increase cardiovascular risk

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“…So far, the origins of ANGPTL4 production include hepatocytes,3, 4 adipocytes,5, 6 skeletal muscle,7 glia cells7, and macrophages 8. Once secreted, the full‐length ANGPTL4 is processed by proprotein convertases at the linker region, releasing its N‐terminal region and the monomeric C‐terminal portion of ANGPTL4.…”

Section: Introductionmentioning

confidence: 99%

Angiopoietin‐Like Protein 4 Is a High‐Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type‐2 Diabetic Patients

Yang

Wang

et al. 2017

JAHA

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Background ANGPTL4 (angiopoietin‐like protein 4) is a LPL (lipoprotein lipase) inhibitor and is present in high‐density lipoprotein (HDL). However, it is not defined whether ANGPTL4 in HDLs could affect HDL metabolism and function in type 2 diabetes mellitus (T2DM).Methods and Results ANGPTL4 levels in the circulation and HDLs were quantified in nondiabetic participants (n=201, 68.7% females) and T2DM patients (n=185, 66.5% females). HDLs were isolated from nondiabetic controls and T2DM patients to assess cholesterol efflux or subjected to endothelial lipase (EL)‐overexpressed HEK293 cells for EL hydrolysis in vitro. The association between ANGPTL4 in HDLs and HDL components and function was analyzed in nondiabetic participants or diabetic patients, respectively. Plasma or HDLs of ANGPTL4+/+ and ANGPTL4−/− mice was subjected for cholesterol efflux or EL hydrolysis, respectively. ANGPTL4 levels in the plasma and HDLs were 1.7‐ and 2.0‐fold higher in T2DM patients than nondiabetic controls, respectively (P<0.0001). Multivariable analysis demonstrated that per 1 doubling increase of ANGPTL4 levels in HDLs, the changes amounted to +0.27% cholesterol efflux (P=0.03), +0.06 μg/mL apolipoprotein A‐I (P=0.09) and −9.41 μg/L serum amyloid A (P=0.02) in nondiabetic controls. In T2DM patients, the corresponding estimates were −0.06% cholesterol efflux (P=0.10), −0.06 μg/mL apolipoprotein A‐I (P=0.38), and +3.64 μg/L serum amyloid A (P=0.72). HDLs isolated from ANGPTL4−/− mice showed accelerated hydrolysis by EL and reduced cholesterol efflux compared with ANGPTL4+/+ littermates.ConclusionsPhysically, ANGPTL4 in HDLs protected HDLs from hydrolysis. Resulting from increased circulating ANGPTL4 levels in T2DM, ANGPTL4 levels in HDLs were elevated but with compromised inhibitory effect on EL, leading to increased HDL hydrolysis and dysfunction.

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Chronic Intermittent Hypoxia Induces Atherosclerosis via Activation of Adipose Angiopoietin-like 4

Cited by 146 publications

References 51 publications

Effect of chronic intermittent hypoxia on triglyceride uptake in different tissues

Effect of chronic intermittent hypoxia on triglyceride uptake in different tissues

Obstructive sleep apnoea treatment and fasting lipids: a comparative effectiveness study

Angiopoietin‐Like Protein 4 Is a High‐Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type‐2 Diabetic Patients

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