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J. Biol. Chem., Vol. 281, Issue 47, 36289-36302, November 24, 2006

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ApoO, a Novel Apolipoprotein, Is an Original Glycoprotein Up-regulated by Diabetes in Human Heart^*

Matthieu Lamant¹, Fatima Smih, Romain Harmancey², Pierre Philip-Couderc², Atul Pathak, Jerome Roncalli, Michel Galinier, Xavier Collet, Pierre Massabuau, Jean-Michel Senard, and Philippe Rouet³

From the Unité de Recherches sur les Obésités, INSERM UPS U586, Institut Louis Bugnard IFR31, CHU Rangueil, Batiment L3, BP 84225, 31432 Toulouse Cedex 4 and INSERM U563, Hôpital Purpan, 31432 Toulouse, France

Obesity is an independent risk factor for cardiac failure. Obesity promotes excessive deposition of fat in adipose and nonadipose tissues. Intramyocardial lipid overload is a relatively common finding in nonischemic heart failure, especially in obese and diabetic patients, and promotes lipoapoptosis that contributes to the alteration of cardiac function. Lipoprotein production has been proposed as a heart-protective mechanism through the unloading of surplus cellular lipids. We previously analyzed the heart transcriptome in a dog nutritional model of obesity, and we identified a new apolipoprotein, regulated by obesity in heart, which is the subject of this study. We detected this new protein in the following lipoproteins: high density lipoprotein, low density lipoprotein, and very low density lipoprotein. We designated it apolipoprotein O. Apolipoprotein O is a 198-amino acid protein that contains a 23-amino acidlong signal peptide. The apolipoprotein O gene is expressed in a set of human tissues. Confocal immunofluorescence microscopy colocalized apolipoprotein O and perilipins, a cellular marker of the lipid droplet. Chondroitinase ABC deglycosylation analysis or cell incubation with p-nitrophenyl--D-xyloside indicated that apolipoprotein O belongs to the proteoglycan family. Naringenin or CP-346086 treatments indicated that apolipoprotein O secretion requires microsomal triglyceride transfer protein activity. Apolipoprotein O gene expression is up-regulated in the human diabetic heart. Apolipoprotein O promoted cholesterol efflux from macrophage cells. To our knowledge, apolipoprotein O is the first chondroitin sulfate chain containing apolipoprotein. Apolipoprotein O may be involved in myocardium-protective mechanisms against lipid accumulation, or it may have specific properties mediated by its unique glycosylation pattern.

Received for publication, October 5, 2005 , and in revised form, August 9, 2006.

The nucleotide sequence(s) reported in this paper has been submitted to the Gen-BankTM/EBI Data Bank with accession number(s) AF061264 [GenBank] .

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Servier Laboratories and ANRT.

² Both authors contributed equally to this work.

³ To whom correspondence should be addressed: INSERM U586, Facultéde Médecine, Laboratoire de Pharmacologie Médicale et Clinique, 37 Allées Jules Guesde, 31073 Toulouse, France. Tel.: 33-5-61-14-59-98; Fax: 33-5-61-25-51-16; E-mail: Philippe.rouet{at}Toulouse.inserm.fr.

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