• ISSN 1674-8301
  • CN 32-1810/R
Volume 34 Issue 1
Jan.  2020
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Zvintzou Evangelia, Xepapadaki Eva, Kalogeropoulou Christina, Filou Serafoula, Kypreos Kyriakos E.. Pleiotropic effects of apolipoprotein A-Ⅱ on high-density lipoprotein functionality, adipose tissue metabolic activity and plasma glucose homeostasis[J]. The Journal of Biomedical Research, 2020, 34(1): 14-26. doi: 10.7555/JBR.33.20190048
Citation: Zvintzou Evangelia, Xepapadaki Eva, Kalogeropoulou Christina, Filou Serafoula, Kypreos Kyriakos E.. Pleiotropic effects of apolipoprotein A-Ⅱ on high-density lipoprotein functionality, adipose tissue metabolic activity and plasma glucose homeostasis[J]. The Journal of Biomedical Research, 2020, 34(1): 14-26. doi: 10.7555/JBR.33.20190048

Pleiotropic effects of apolipoprotein A-Ⅱ on high-density lipoprotein functionality, adipose tissue metabolic activity and plasma glucose homeostasis

doi: 10.7555/JBR.33.20190048
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  • Corresponding author: Kyriakos E. Kypreos, Department of Pharmacology, University of Patras Medical School, Panepistimioupolis, Rio Achaias, TK 26500, Greece. Tel/ Fax: +302610969120/+302610996103, E-mail: kkypreos@med.upatras.gr
  • Received: 2019-03-29
  • Revised: 2019-05-14
  • Accepted: 2019-05-16
  • Published: 2019-09-09
  • Issue Date: 2020-01-28
  • Apolipoprotein A-Ⅱ (APOA-Ⅱ) is the second most abundant apolipoprotein of high-density lipoprotein (HDL) synthesized mainly by the liver and to a much lesser extent by the intestine. Transgenic mice overexpressing human APOA-Ⅱ present abnormal lipoprotein composition and are prone to atherosclerosis, though in humans the role for APOA-Ⅱ in coronary heart disease remains controversial. Here, we investigated the effects of overexpressed APOA-Ⅱ on HDL structure and function, adipose tissue metabolic activity, glucose tolerance and insulin sensitivity. C57BL/6 mice were infected with an adenovirus expressing human APOA-Ⅱ or a control adenovirus AdGFP, and five days post-infection blood and tissue samples were isolated. APOA-Ⅱ expression resulted in distinct changes in HDL apoproteome that correlated with increased antioxidant and anti-inflammatory activities. No effects on cholesterol efflux from RAW 264.7 macrophages were observed. Molecular analyses in white adipose tissue (WAT) indicated a stimulation of oxidative phosphorylation coupled with respiration for ATP production in mice overexpressing APOA-Ⅱ. Finally, overexpressed APOA-Ⅱ improved glucose tolerance of mice but had no effect on the response to exogenously administered insulin. In summary, expression of APOA-Ⅱ in C57BL/6 mice results in pleiotropic effects with respect to HDL functionality, adipose tissue metabolism and glucose utilization, many of which are beneficial to health.


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  • [1]
    Brewer HB Jr, Lux SE, Ronan R, et al. Amino acid sequence of human apoLp-Gln-Ⅱ (apoA-Ⅱ), an apolipoprotein isolated from the high-density lipoprotein complex[J]. Proc Natl Acad Sci USA, 1972, 69(5): 1304–1308. doi: 10.1073/pnas.69.5.1304
    Pownall HJ, Gillard BK, Gotto AM Jr. Setting the course for apoAⅡ: a port in sight?[J]. Clin Lipidol, 2013, 8(5): 551–560. doi: 10.2217/clp.13.59
    Borghini I, Barja F, Pometta D, et al. Characterization of subpopulations of lipoprotein particles isolated from human cerebrospinal fluid[J]. Biochim Biophys Acta, 1995, 1255(2): 192–200. doi: 10.1016/0005-2760(94)00232-N
    Warden CH, Hedrick CC, Qiao JH, et al. Atherosclerosis in transgenic mice overexpressing apolipoprotein A-Ⅱ[J]. Science, 1993, 261(5120): 469–472. doi: 10.1126/science.8332912
    van't Hooft FM, Ruotolo G, Boquist S, et al. Human evidence that the apolipoprotein A-Ⅱ gene is implicated in visceral fat accumulation and metabolism of triglyceride-rich lipoproteins[J]. Circulation, 2001, 104(11): 1223–1228. doi: 10.1161/hc3601.095709
    Gordon SM, Chung JH, Playford MP, et al. High density lipoprotein proteome is associated with cardiovascular risk factors and atherosclerosis burden as evaluated by coronary CT angiography[J]. Atherosclerosis, 2018, 278: 278–285. doi: 10.1016/j.atherosclerosis.2018.09.032
    Constantinou C, Karavia EA, Xepapadaki E, et al. Advances in high-density lipoprotein physiology: surprises, overturns, and promises[J]. Am J Physiol Endocrinol Metab, 2016, 310(1): E1–E14. doi: 10.1152/ajpendo.00429.2015
    Tsompanidi EM, Brinkmeier MS, Fotiadou EH, et al. HDL biogenesis and functions: role of HDL quality and quantity in atherosclerosis[J]. Atherosclerosis, 2010, 208(1): 3–9. doi: 10.1016/j.atherosclerosis.2009.05.034
    Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events[J]. N Engl J Med, 2007, 357(21): 2109–2122. doi: 10.1056/NEJMoa0706628
    Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome[J]. N Engl J Med, 2012, 367(22): 2089–2099. doi: 10.1056/NEJMoa1206797
    Lincoff AM, Nicholls SJ, Riesmeyer JS, et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease[J]. N Engl J Med, 2017, 376(20): 1933–1942. doi: 10.1056/NEJMoa1609581
    The AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy[J]. N Engl J Med, 2011, 365(24): 2255–2267. doi: 10.1056/NEJMoa1107579
    The HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients[J]. N Engl J Med, 2014, 371(3): 203–212. doi: 10.1056/NEJMoa1300955
    Bowe B, Xie Y, Xian H, et al. High density lipoprotein cholesterol and the risk of all-cause mortality among U.S. Veterans[J]. Clin J Am Soc Nephrol, 2016, 11(10): 1784–1793. doi: 10.2215/CJN.00730116
    Loscalzo J. Molecular mechanisms of atherosclerosis[M]. London: CRC Press, 2004: 111–174.
    Kavo AE, Rallidis LS, Sakellaropoulos GC, et al. Qualitative characteristics of HDL in young patients of an acute myocardial infarction[J]. Atherosclerosis, 2012, 220(1): 257–264. doi: 10.1016/j.atherosclerosis.2011.10.017
    Filou S, Lhomme M, Karavia EA, et al. Distinct roles of apolipoproteins A1 and E in the modulation of high-density lipoprotein composition and function[J]. Biochemistry, 2016, 55(27): 3752–3762. doi: 10.1021/acs.biochem.6b00389
    Zvintzou E, Lhomme M, Chasapi S, et al. Pleiotropic effects of apolipoprotein C3 on HDL functionality and adipose tissue metabolic activity[J]. J Lipid Res, 2017, 58(9): 1869–1883. doi: 10.1194/jlr.M077925
    Pamir N, Pan C, Plubell DL, et al. Genetic control of the mouse HDL proteome defines HDL traits, function, and heterogeneity[J]. J Lipid Res, 2019, 60(3): 594–608. doi: 10.1194/jlr.M090555
    Kontush A, Lindahl M, Lhomme M, et al. Structure of HDL: particle subclasses and molecular components[M]//von Eckardstein A, Kardassis D. High density lipoproteins. Cham: Springer, 2015: 3–51.
    Boyce G, Button E, Soo S, et al. The pleiotropic vasoprotective functions of high density lipoproteins (HDL)[J]. J Biomed Res, 2018, 32(3): 164–182.
    Kypreos KE. ABCA1 promotes the de novo biogenesis of apolipoprotein CⅢ-containing HDL particles in vivo and modulates the severity of apolipoprotein CⅢ-induced hypertriglyceridemia[J]. Biochemistry, 2008, 47(39): 10491–10502. doi: 10.1021/bi801249c
    Constantinou C, Mpatsoulis D, Natsos A, et al. The low density lipoprotein receptor modulates the effects of hypogonadism on diet-induced obesity and related metabolic perturbations[J]. J Lipid Res, 2014, 55(7): 1434–1447. doi: 10.1194/jlr.M050047
    Tselepis AD, Dentan C, Karabina SAP, et al. PAF-degrading acetylhydrolase is preferentially associated with dense LDL and VHDL-1 in human plasma. Catalytic characteristics and relation to the monocyte-derived enzyme[J]. Arterioscler Thromb Vasc Biol, 1995, 15(10): 1764–1773. doi: 10.1161/01.ATV.15.10.1764
    Kelesidis T, Currier JS, Huynh D, et al. A biochemical fluorometric method for assessing the oxidative properties of HDL[J]. J Lipid Res, 2011, 52(12): 2341–2351. doi: 10.1194/jlr.D018937
    Knott TJ, Priestley LM, Urdea M, et al. Isolation and characterisation of a cDNA encoding the precursor for human apolipoprotein AⅡ[J]. Biochem Biophys Res Commun, 1984, 120(3): 734–740. doi: 10.1016/S0006-291X(84)80168-0
    Petropoulou PI, Berbée JFP, Theodoropoulos V, et al. Lack of LCAT reduces the LPS-neutralizing capacity of HDL and enhances LPS-induced inflammation in mice[J]. Biochim Biophys Acta, 2015, 1852(10): 2106–2115. doi: 10.1016/j.bbadis.2015.07.010
    Rensen PCN, van Berkel TJC. Apolipoprotein E effectively inhibits lipoprotein lipase-mediated lipolysis of chylomicron-like triglyceride-rich lipid emulsions in vitro and in vivo[J]. J Biol Chem, 1996, 271(25): 14791–14799. doi: 10.1074/jbc.271.25.14791
    Larsson M, Allan CM, Jung RS, et al. Apolipoprotein C-III inhibits triglyceride hydrolysis by GPIHBP1-bound LPL[J]. J Lipid Res, 2017, 58(9): 1893–1902. doi: 10.1194/jlr.M078220
    Kypreos KE, Van Dijk KW, Havekes LM, et al. Generation of a recombinant apolipoprotein E variant with improved biological functions: hydrophobic residues (LEU-261, TRP-264, PHE-265, LEU-268, VAL-269) of apoE can account for the apoE-induced hypertriglyceridemia[J]. J Biol Chem, 2005, 280(8): 6276–6284. doi: 10.1074/jbc.M413458200
    Julve J, Escolà-Gil JC, Rotllan N, et al. Human apolipoprotein A-Ⅱ determines plasma triglycerides by regulating lipoprotein lipase activity and high-density lipoprotein proteome[J]. Arterioscler Thromb Vasc Biol, 2010, 30(2): 232–238. doi: 10.1161/ATVBAHA.109.198226
    Marzal-Casacuberta A, Blanco-Vaca F, Ishida BY, et al. Functional lecithin: cholesterol acyltransferase deficiency and high density lipoprotein deficiency in transgenic mice overexpressing human apolipoprotein A-Ⅱ[J]. J Biol Chem, 1996, 271(12): 6720–6728. doi: 10.1074/jbc.271.12.6720
    Rosenson RS, Stafforini DM. Modulation of oxidative stress, inflammation, and atherosclerosis by lipoprotein-associated phospholipase A2[J]. J Lipid Res, 2012, 53(9): 1767–1782. doi: 10.1194/jlr.R024190
    Flachs P, Rossmeisl M, Kuda O, et al. Stimulation of mitochondrial oxidative capacity in white fat independent of UCP1: a key to lean phenotype[J]. Biochim Biophys Acta, 2013, 1831(5): 986–1003. doi: 10.1016/j.bbalip.2013.02.003
    Castellani LW, Goto AM, Lusis AJ. Studies with apolipoprotein A-Ⅱ transgenic mice indicate a role for HDLs in adiposity and insulin resistance[J]. Diabetes, 2001, 50(3): 643–651. doi: 10.2337/diabetes.50.3.643
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