ABSTRACT
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-beta-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.
Subject(s)
Apolipoproteins/physiology , Diabetes Mellitus/metabolism , Glycoproteins/chemistry , Myocardium/metabolism , Up-Regulation , 3T3 Cells , Amino Acid Sequence , Animals , Apolipoproteins/chemistry , COS Cells , Chlorocebus aethiops , Chondroitin ABC Lyase/chemistry , Flavanones/pharmacology , Humans , Isoquinolines/pharmacology , Lipoproteins/chemistry , Mice , Molecular Sequence Data , Sequence Homology, Amino Acid , Triazoles/pharmacologyABSTRACT
Transferrin (Tf), the iron transport glycoprotein found in biological fluids of vertebrates, is synthesized mainly by hepatocytes. Tf is also synthesized by oligodendrocytes (Ol), and several lines of evidence indicate that brain Tf could be involved in myelinogenesis. Because Tf is postnatally expressed in the brain, we sought to investigate whether Tf could intervene in Ol differentiation. For this purpose, we analyzed transgenic mice overexpressing the complete human Tf gene in Ol. We show that the hTf transgene was expressed only from 5 days postpartum onward. In the brain of 14-day-old transgenic mice, the DM-20 mRNA level was decreased, whereas the PLP, MBP, CNP, and MAG mRNA levels were increased. We counted a higher proportion of Ol expressing the O4 (Ol-specific antigens) and PLP in brain cells cultured from transgenic mice. These results support the idea that overexpressing Tf in the brain accelerates the oligodendrocyte lineage maturation. Accordingly, by NMR imaging acquisition of diffusion tensor in hTf transgenic mice, we observed early maturation of the cerebellum and spinal cord and more myelination in the corpus callosum. In addition, hTf overexpression led to an increase in Sox10 mRNA and protein. Increases in Sox10 and in Tf expression occur simultaneously during brain development. The Olig1 mRNA level also increased, but long after the rise of hTf and Sox10. The Olig2 mRNA level remained unchanged in the brain of transgenic mice. Our findings suggest that Tf could influence oligodendrocyte progenitor differentiation in the CNS.
