title: Aging impairs the hepatic subcellular distribution of ChREBP in response to fasting/feeding in rats: Implications on hepatic steatosis.
abstract: Aging is associated with alterations of lipid metabolism and increased prevalence of non alcoholic hepatic steatosis. Nevertheless, the mechanisms by which fat is accumulated in the liver during aging remain incompletely understood. In the present study, we investigated potential alterations that might contribute to the development of hepatic steatosis with aging. To this end, we analyzed the expression and the subcellular localization of key transcriptional factors involved in lipid metabolism such as ChREBP, Foxo1, Foxa2 and SREBP-1c in the liver of 3- and 24-month old Wistar rats. In addition, we studied the intracellular redistribution of ChREBP in response to fasting/refeeding transition. Old rats were characterized by hepatic steatosis, low serum ketone body levels and postprandial hyperinsulinemia. These observations were paralleled by the cytoplasmic localization and decreased expression of Foxa2, while ChREBP expression was markedly up-regulated and mainly localized in the nucleus. Consequently, the expression of lipogenic and β-oxidation genes was up-regulated or down-regulated, respectively. Besides, the intracellular redistribution of ChREBP in response to fasting/refeeding transition was also impaired in old animals. Additionally, a negative correlation between serum ketone body levels and the nuclear localization of ChREBP was observed only in adult but not in old rats. Taken together, these data suggest that an age-related dysfunctional adaptation of ChREBP, in response to changes in the nutritional state, might contribute to the development of liver steatosis with aging.
authors.affiliation: Biochemistry Section, Faculty of Chemistry (Ciudad Real) and Faculty of Biochemistry and Environmental Sciences (Toledo), Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha, Ciudad Real/Toledo, Spain.
authors.forename: Aurora
authors.initials: A
authors.lastname: Salamanca
authors.affiliation: Biochemistry Section, Faculty of Chemistry (Ciudad Real) and Faculty of Biochemistry and Environmental Sciences (Toledo), Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha, Ciudad Real/Toledo, Spain.
authors.forename: Brenda
authors.initials: B
authors.lastname: Bárcena
authors.affiliation: Biochemistry Section, Faculty of Chemistry (Ciudad Real) and Faculty of Biochemistry and Environmental Sciences (Toledo), Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha, Ciudad Real/Toledo, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Arribas
authors.affiliation: Health Sciences Faculty, University Rey Juan Carlos, Alcorcón, Madrid, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Fernández-Agulló
authors.affiliation: Health Sciences Faculty, University Rey Juan Carlos, Alcorcón, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Martínez
authors.affiliation: Centre of Molecular Biology "Severo Ochoa", Autonomous University, Madrid, Spain.
authors.forename: José Ma
authors.initials: JM
authors.lastname: Carrascosa
authors.affiliation: Health Sciences Faculty, University Rey Juan Carlos, Alcorcón, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ros
authors.affiliation: Biochemistry Section, Faculty of Chemistry (Ciudad Real) and Faculty of Biochemistry and Environmental Sciences (Toledo), Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha, Ciudad Real/Toledo, Spain. Electronic address: antonio.andres@uclm.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: Andrés
authors.affiliation: Biochemistry Section, Faculty of Chemistry (Ciudad Real) and Faculty of Biochemistry and Environmental Sciences (Toledo), Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha, Ciudad Real/Toledo, Spain. Electronic address: nilda.gallardo@uclm.es.
authors.forename: Nilda
authors.initials: N
authors.lastname: Gallardo
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D002529:Cerebellar Nuclei / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation; D004435:Eating / Q000502:physiology*; D005215:Fasting / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D015854:Up-Regulation; D000071161:Forkhead Box Protein O1
chemical_list: D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D051780:Sterol Regulatory Element Binding Protein 1; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1
keywords: Aging; ChREBP; Hepatic steatosis; Insulin resistance; Nutritional adaptation