title: Effects of hyperglycemia and aging on nuclear sirtuins and DNA damage of mouse hepatocytes.
abstract: Hyperglycemia, like aging, induces chromatin remodeling in mouse hepatocytes in comparison to normoglycemia and younger age, respectively. Changes in glucose metabolism also affect the action and expression of sirtuins, promoting changes in chromatin conformation and dynamics. Here we investigate the abundance and activity of the nuclear sirtuins Sirt1, Sirt6, and Sirt7 in mouse hepatocytes in association with specific histone acetylation, DNA damage, and the activation of nucleolar organizing regions (NORs) in hyperglycemic nonobese diabetic (NOD) and old normoglycemic BALB/c mouse strains. Higher levels of Sirt1 and PGC-1α and increased expression of gluconeogenesis pathway genes are found in the hyperglycemic NOD mice. Increased Sirt6 abundance is found in the hyperglycemic NOD mice, which might increase DNA damage repair. With aging, lower Sirt1 abundance and activity, increased acetylated histone modifications and Sirt7 levels, and NOR methylation are found. Thus, whereas in normal aging cell metabolism is reduced, in the diabetic mice a compensatory mechanism may elevate Sirt1 and Sirt6 levels, increasing gluconeogenesis and DNA repair from the oxidative damage caused by hyperglycemia. Therefore understanding the regulation of epigenetic factors in diabetes and aging is crucial for the development of new therapeutic approaches that could prevent diseases and improve quality of life.
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, University of Campinas, 13083-862 Campinas, SP, Brazil.
authors.forename: Flávia Gerelli
authors.initials: FG
authors.lastname: Ghiraldini
authors.forename: Ana Carolina Vitolo
authors.initials: AC
authors.lastname: Crispim
authors.forename: Maria Luiza Silveira
authors.initials: ML
authors.lastname: Mello
mesh_terms: D000107:Acetylation; D000375:Aging; D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D002467:Cell Nucleus / Q000201:enzymology*; D053938:DNA Fragmentation; D004260:DNA Repair; D044127:Epigenesis, Genetic; D005260:Female; D005943:Gluconeogenesis; D022781:Hepatocytes / Q000201:enzymology*; D006657:Histones / Q000378:metabolism; D006943:Hyperglycemia / Q000201:enzymology*; D008099:Liver / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D009697:Nucleolus Organizer Region / Q000378:metabolism; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011499:Protein Processing, Post-Translational; D056564:Sirtuin 1 / Q000378:metabolism*; D037761:Sirtuins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D034961:Antigens, Nuclear; D006657:Histones; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; C051963:nucleolar organizer region associated proteins; C501860:Sirt6 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins