The APOA1bp–SREBF–NOTCH axis is associated with reduced atherosclerosis risk in morbidly obese patients

  • Jordi Mayneris-Perxachs
    Affiliations
    Department of Endocrinology, Diabetes and Nutrition, Hospital of Girona “Dr Josep Trueta”, Departament de Ciències Mèdiques, University of Girona, Girona Biomedical Research Institute (IdibGi), Girona, Spain

    CIBERobn Pathophysiology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain
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  • Josep Puig
    Affiliations
    Department of Radiology, Diagnostic Imaging Institute (IDI), Dr Josep Trueta University Hospital, IDIBGI, Girona, Spain
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  • Rémy Burcelin
    Affiliations
    Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France

    Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: ‘Intestinal Risk Factors, Diabetes, Dyslipidemia, and Heart Failure’, F-31432 Toulouse Cedex 4, France
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  • Marc-Emmanuel Dumas
    Affiliations
    Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom

    Section of Genomic and Environmental Medicine, Respiratory Division, National Heart and Lung Institute, Imperial College London, Dovehouse St, London SW3 6KY, United Kingdom
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  • Richard H. Barton
    Affiliations
    Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom
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  • Lesley Hoyles
    Affiliations
    Department of Biosciences, Nottingham Trent University, Clifton Campus, Nottingham NG11 8NS, United Kingdom
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  • Massimo Federici
    Affiliations
    Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
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  • José-Manuel Fernández-Real
    Correspondence
    Corresponding author. Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Girona Biomedical Research Institute (IdIBGi), Carretera de França s/n, 17007 Girona, Spain. Fax: +34 97294027.
    Affiliations
    Department of Endocrinology, Diabetes and Nutrition, Hospital of Girona “Dr Josep Trueta”, Departament de Ciències Mèdiques, University of Girona, Girona Biomedical Research Institute (IdibGi), Girona, Spain

    CIBERobn Pathophysiology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain
    Search for articles by this author
Published:March 08, 2020DOI:https://doi.org/10.1016/j.clnu.2020.02.034

      Summary

      Background & aims

      Atherosclerosis is characterized by an inflammatory disease linked to excessive lipid accumulation in the artery wall. The Notch signalling pathway has been shown to play a key regulatory role in the regulation of inflammation. Recently, in vitro and pre-clinical studies have shown that apolipoprotein A–I binding protein (AIBP) regulates cholesterol metabolism (SREBP) and NOTCH signalling (haematopoiesis) and may be protective against atherosclerosis, but the evidence in humans is scarce.

      Methods

      We evaluated the APOA1bp–SREBF–NOTCH axis in association with atherosclerosis in two well-characterized cohorts of morbidly obese patients (n = 78) within the FLORINASH study, including liver transcriptomics, 1H NMR plasma metabolomics, high-resolution ultrasonography evaluating carotid intima-media thickness (cIMT), and haematological parameters.

      Results

      The liver expression levels of APOA1bp were associated with lower cIMT and leukocyte counts, a better plasma lipid profile and higher circulating levels of metabolites associated with lower risk of atherosclerosis (glycine, histidine and asparagine). Conversely, liver SREBF and NOTCH mRNAs were positively associated with atherosclerosis, liver steatosis, an unfavourable lipid profile, higher leukocytes and increased levels of metabolites linked to inflammation and CVD such as branched-chain amino acids and glycoproteins. APOA1bp and NOTCH signalling also had a strong association, as revealed by the negative correlations among APOA1bp expression levels and those of all NOTCH receptors and jagged ligands.

      Conclusions

      We here provide the first evidence in human liver of the putative APOA1bpSREBF–NOTCH axis signalling pathway and its association with atherosclerosis and inflammation.

      Keywords

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      References

        • Khera A.V.
        • Cuchel M.
        • de la Llera-Moya M.
        • Rodrigues A.
        • Burke M.F.
        • Jafri K.
        • et al.
        Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis.
        N Engl J Med. 2011; 364: 127-135https://doi.org/10.1056/NEJMoa1001689
        • Ohashi R.
        • Mu H.
        • Wang X.
        • Yao Q.
        • Chen C.
        Reverse cholesterol transport and cholesterol efflux in atherosclerosis.
        QJM An Int J Med. 2005; 98: 845-856https://doi.org/10.1093/qjmed/hci136
        • Rohatgi A.
        • Khera A.
        • Berry J.D.
        • Givens E.G.
        • Ayers C.R.
        • Wedin K.E.
        • et al.
        HDL cholesterol efflux capacity and incident cardiovascular events.
        N Engl J Med. 2014; 371: 2383-2393https://doi.org/10.1056/NEJMoa1409065
        • Ritter M.
        • Buechler C.
        • Boettcher A.
        • Barlage S.
        • Schmitz-Madry A.
        • Orsó E.
        • et al.
        Cloning and characterization of a novel apolipoprotein A–I binding protein, AI-BP, secreted by cells of the kidney proximal tubules in response to HDL or ApoA–I.
        Genomics. 2002; 79: 693-702https://doi.org/10.1006/geno.2002.6761
        • Zhang M.
        • Li L.
        • Xie W.
        • Wu J.-F.
        • Yao F.
        • Tan Y.-L.
        • et al.
        Apolipoprotein A-1 binding protein promotes macrophage cholesterol efflux by facilitating apolipoprotein A-1 binding to ABCA1 and preventing ABCA1 degradation.
        Atherosclerosis. 2016; 248: 149-159https://doi.org/10.1016/j.atherosclerosis.2016.03.008
        • Fang L.
        • Choi S.-H.
        • Baek J.S.
        • Liu C.
        • Almazan F.
        • Ulrich F.
        • et al.
        Control of angiogenesis by AIBP-mediated cholesterol efflux.
        Nature. 2013; 498: 118-122https://doi.org/10.1038/nature12166
        • Schneider D.A.
        • Choi S.-H.
        • Agatisa-Boyle C.
        • Zhu L.
        • Kim J.
        • Pattison J.
        • et al.
        AIBP protects against metabolic abnormalities and atherosclerosis.
        J Lipid Res. 2018; 59: 854-863https://doi.org/10.1194/jlr.M083618
        • Zhang M.
        • Zhao G.-J.
        • Yao F.
        • Xia X.-D.
        • Gong D.
        • Zhao Z.-W.
        • et al.
        AIBP reduces atherosclerosis by promoting reverse cholesterol transport and ameliorating inflammation in apoE−/− mice.
        Atherosclerosis. 2018; 273: 122-130https://doi.org/10.1016/j.atherosclerosis.2018.03.010
        • Gisterå A.
        • Hansson G.K.
        The immunology of atherosclerosis.
        Nat Rev Nephrol. 2017; 13: 368-380https://doi.org/10.1038/nrneph.2017.51
        • Radtke F.
        • MacDonald H.R.
        • Tacchini-Cottier F.
        Regulation of innate and adaptive immunity by Notch.
        Nat Rev Immunol. 2013; 13: 427-437https://doi.org/10.1038/nri3445
        • Vieceli Dalla Sega F.
        • Fortini F.
        • Aquila G.
        • Campo G.
        • Vaccarezza M.
        • Rizzo P.
        Notch signaling regulates immune responses in atherosclerosis.
        Front Immunol. 2019; 10https://doi.org/10.3389/fimmu.2019.01130
        • Soehnlein O.
        • Swirski F.K.
        Hypercholesterolemia links hematopoiesis with atherosclerosis.
        Trends Endocrinol Metab. 2013; 24: 129-136https://doi.org/10.1016/j.tem.2012.10.008
        • Mao R.
        • Meng S.
        • Gu Q.
        • Araujo-Gutierrez R.
        • Kumar S.
        • Yan Q.
        • et al.
        AIBP limits angiogenesis through γ-secretase-mediated upregulation of notch signaling.
        Circ Res. 2017; 120: 1727-1739https://doi.org/10.1161/CIRCRESAHA.116.309754
        • Gu Q.
        • Yang X.
        • Lv J.
        • Zhang J.
        • Xia B.
        • Kim J.
        • et al.
        AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate.
        Science. 2019; 363: 1085-1088https://doi.org/10.1126/science.aav1749
        • Muench M.O.
        • Beyer A.I.
        • Fomin M.E.
        • Thakker R.
        • Mulvaney U.S.
        • Nakamura M.
        • et al.
        The adult livers of immunodeficient mice support human hematopoiesis: evidence for a hepatic mast cell population that develops early in human ontogeny.
        PLoS One. 2014; 9e97312https://doi.org/10.1371/journal.pone.0097312
        • Golden-Mason L.
        • O'Farrelly C.
        Having it all? Stem cells, haematopoiesis and lymphopoiesis in adult human liver.
        Immunol Cell Biol. 2002; 80: 45-51https://doi.org/10.1046/j.1440-1711.2002.01066.x
        • Hoyles L.
        • Fernández-Real J.-M.
        • Federici M.
        • Serino M.
        • Abbott J.
        • Charpentier J.
        • et al.
        Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women.
        Nat Med. 2018; 24: 1070-1080https://doi.org/10.1038/s41591-018-0061-3
        • Kleiner D.E.
        • Brunt E.M.
        • Van Natta M.
        • Behling C.
        • Contos M.J.
        • Cummings O.W.
        • et al.
        Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
        Hepatology. 2005; 41: 1313-1321https://doi.org/10.1002/hep.20701
        • Fleige S.
        • Pfaffl M.W.
        RNA integrity and the effect on the real-time qRT-PCR performance.
        Mol Aspects Med. 2006; 27: 126-139https://doi.org/10.1016/j.mam.2005.12.003
        • Smyth G.K.
        Limma: linear models for microarray data. Bioinforma. Comput. Biol. Solut. Using R bioconductor.
        Springer-Verlag, New York2005: 397-420https://doi.org/10.1007/0-387-29362-0_23
        • Touboul P.-J.
        • Hennerici M.G.
        • Meairs S.
        • Adams H.
        • Amarenco P.
        • Bornstein N.
        • et al.
        Mannheim carotid intima-media thickness and plaque consensus (2004–2006–2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011.
        Cerebrovasc Dis. 2012; 34: 290-296https://doi.org/10.1159/000343145
        • Connelly M.A.
        • Otvos J.D.
        • Shalaurova I.
        • Playford M.P.
        • Mehta N.N.
        GlycA, a novel biomarker of systemic inflammation and cardiovascular disease risk.
        J Transl Med. 2017; 15: 219https://doi.org/10.1186/s12967-017-1321-6
        • Wang S.
        • Smith J.D.
        ABCA1 and nascent HDL biogenesis.
        Biofactors. 2014; 40: 547-554https://doi.org/10.1002/biof.1187
        • Lv Y.
        • Yin K.
        • Fu Y.
        • Zhang D.
        • Chen W.
        • Tang C.
        Posttranscriptional regulation of ATP-binding cassette transporter A1 in lipid metabolism.
        DNA Cell Biol. 2013; 32: 348-358https://doi.org/10.1089/dna.2012.1940
        • Hoekstra M.
        SR-BI as target in atherosclerosis and cardiovascular disease – a comprehensive appraisal of the cellular functions of SR-BI in physiology and disease.
        Atherosclerosis. 2017; 258: 153-161https://doi.org/10.1016/j.atherosclerosis.2017.01.034
        • Shelness G.S.
        • Sellers J.A.
        Very-low-density lipoprotein assembly and secretion.
        Curr Opin Lipidol. 2001; 12: 151-157
        • Okazaki H.
        • Goldstein J.L.
        • Brown M.S.
        • Liang G.
        LXR-SREBP-1c-phospholipid transfer protein axis controls very low density lipoprotein (VLDL) particle size.
        J Biol Chem. 2010; 285: 6801-6810https://doi.org/10.1074/jbc.M109.079459
        • Selwaness M.
        • Van Den Bouwhuijsen Q.
        • Van Onkelen R.S.
        • Hofman A.
        • Franco O.H.
        • Van Der Lugt A.
        • et al.
        Atherosclerotic plaque in the left carotid artery is more vulnerable than in the right.
        Stroke. 2014; 45: 3226-3230https://doi.org/10.1161/STROKEAHA.114.005202
        • Chou C.L.
        • Wu Y.J.
        • Hung C.L.
        • Liu C.C.
        • Wang S. De
        • Wu T.W.
        • et al.
        Segment-specific prevalence of carotid artery plaque and stenosis in middle-aged adults and elders in Taiwan: a community-based study.
        J Formos Med Assoc. 2019; 118: 64-71https://doi.org/10.1016/j.jfma.2018.01.009
        • Ferré P.
        • Foufelle F.
        Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c.
        Diabetes Obes Metab. 2010; 12: 83-92https://doi.org/10.1111/j.1463-1326.2010.01275.x
        • Rutz S.
        • Mordmüller B.
        • Sakano S.
        • Scheffold A.
        Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cells.
        Eur J Immunol. 2005; 35: 2443-2451https://doi.org/10.1002/eji.200526294
        • Benedito R.
        • Roca C.
        • Sörensen I.
        • Adams S.
        • Gossler A.
        • Fruttiger M.
        • et al.
        The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis.
        Cell. 2009; 137: 1124-1135https://doi.org/10.1016/j.cell.2009.03.025
        • Fiddes I.T.
        • Lodewijk G.A.
        • Mooring M.
        • Bosworth C.M.
        • Ewing A.D.
        • Mantalas G.L.
        • et al.
        Human-specific NOTCH2NL genes affect notch signaling and cortical neurogenesis.
        Cell. 2018; 173 (e22): 1356-1369https://doi.org/10.1016/j.cell.2018.03.051
        • Suzuki I.K.
        • Gacquer D.
        • Van Heurck R.
        • Kumar D.
        • Wojno M.
        • Bilheu A.
        • et al.
        Human-specific NOTCH2NL genes expand cortical neurogenesis through delta/notch regulation.
        Cell. 2018; 173 (e16): 1370-1384https://doi.org/10.1016/j.cell.2018.03.067
        • Ottosson F.
        • Smith E.
        • Melander O.
        • Fernandez C.
        Altered asparagine and glutamate homeostasis precede coronary artery disease and type 2 diabetes.
        J Clin Endocrinol Metab. 2018; 103: 3060-3069https://doi.org/10.1210/jc.2018-00546
        • Wittemans L.B.L.
        • Lotta L.A.
        • Oliver-Williams C.
        • Stewart I.D.
        • Surendran P.
        • Karthikeyan S.
        • et al.
        Assessing the causal association of glycine with risk of cardio-metabolic diseases.
        Nat Commun. 2019; 10: 1060https://doi.org/10.1038/s41467-019-08936-1
        • Cole L.K.
        • Vance J.E.
        • Vance D.E.
        Phosphatidylcholine biosynthesis and lipoprotein metabolism.
        Biochim Biophys Acta Mol Cell Biol Lipids. 2012; 1821: 754-761https://doi.org/10.1016/j.bbalip.2011.09.009
        • Ossoli A.
        • Simonelli S.
        • Vitali C.
        • Franceschini G.
        • Calabresi L.
        Role of LCAT in atherosclerosis.
        J Atheroscler Thromb. 2016; 23: 119-127https://doi.org/10.5551/jat.32854
        • Guasch-Ferré M.
        • Hu F.B.
        • Ruiz-Canela M.
        • Bulló M.
        • Toledo E.
        • Wang D.D.
        • et al.
        Plasma metabolites from choline pathway and risk of cardiovascular disease in the PREDIMED (prevention with Mediterranean diet) study.
        J Am Heart Assoc. 2017; 6https://doi.org/10.1161/JAHA.117.006524
        • Wang Z.
        • Tang W.H.W.
        • Buffa J.A.
        • Fu X.
        • Britt E.B.
        • Koeth R.A.
        • et al.
        Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide.
        Eur Heart J. 2014; 35: 904-910https://doi.org/10.1093/eurheartj/ehu002
        • Roe A.J.
        • Zhang S.
        • Bhadelia R.A.
        • Johnson E.J.
        • Lichtenstein A.H.
        • Rogers G.T.
        • et al.
        Choline and its metabolites are differently associated with cardiometabolic risk factors, history of cardiovascular disease, and MRI-documented cerebrovascular disease in older adults.
        Am J Clin Nutr. 2017; 105: 1283-1290https://doi.org/10.3945/ajcn.116.137158
        • Konstantinova S.V.
        • Tell G.S.
        • Vollset S.E.
        • Nygård O.
        • Bleie Ø.
        • Ueland P.M.
        Divergent associations of plasma choline and betaine with components of metabolic syndrome in middle age and elderly men and women.
        J Nutr. 2008; 138: 914-920https://doi.org/10.1093/jn/138.5.914
        • Fischer L.M.
        • daCosta K.A.
        • Kwock L.
        • Stewart P.W.
        • Lu T.-S.
        • Stabler S.P.
        • et al.
        Sex and menopausal status influence human dietary requirements for the nutrient choline.
        Am J Clin Nutr. 2007; 85: 1275-1285https://doi.org/10.1093/ajcn/85.5.1275
        • Bae S.
        • Ulrich C.M.
        • Neuhouser M.L.
        • Malysheva O.
        • Bailey L.B.
        • Xiao L.
        • et al.
        Plasma choline metabolites and colorectal cancer risk in the women's health initiative observational study.
        Cancer Res. 2014; 74: 7442-7452https://doi.org/10.1158/0008-5472.CAN-14-1835
        • Yan J.
        • Winter L.B.
        • Burns-Whitmore B.
        • Vermeylen F.
        • Caudill M.A.
        Plasma choline metabolites associate with metabolic stress among young overweight men in a genotype-specific manner.
        Nutr Diabetes. 2012; 2: e49https://doi.org/10.1038/nutd.2012.23
        • Lever M.
        • George P.M.
        • Atkinson W.
        • Molyneux S.L.
        • Elmslie J.L.
        • Slow S.
        • et al.
        Plasma lipids and betaine are related in an acute coronary syndrome cohort.
        PLoS One. 2011; 6e21666https://doi.org/10.1371/journal.pone.0021666
        • Zhang Z.-Y.
        • Monleon D.
        • Verhamme P.
        • Staessen J.A.
        Branched-chain amino acids as critical switches in health and disease.
        Hypertension. 2018; 72: 1012-1022https://doi.org/10.1161/HYPERTENSIONAHA.118.10919
        • Yang R.
        • Dong J.
        • Zhao H.
        • Li H.
        • Guo H.
        • Wang S.
        • et al.
        Association of branched-chain amino acids with carotid intima-media thickness and coronary artery disease risk factors.
        PLoS One. 2014; 9e99598https://doi.org/10.1371/journal.pone.0099598