Rattus norvegicus
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PROVIDER: PRJNA138237 | ENA |
REPOSITORIES: ENA
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Project description:To determine the effects of age and lipoic acid supplementation on hepatic gene expression, we fed young (3 months) and old (24 months) male Fischer 344 rats a diet with or without 0.2% (w/w) R-α-lipoic acid (LA) for two weeks. Total RNA isolated from liver tissue was analyzed by Affymetrix microarray to examine changes in transcriptional profile. Results showed an increase in pro-inflammatory gene expression in the aging liver, with increased immune cell function and tissue remodeling genes, representing 45% of the age-related transcriptome changes. Increased inflammation was corroborated by increases in soluble ICAM1 levels with age. There were also observed age-related increases in transcription of genes related to lipid and cholesterol synthesis including Acetyl CoA Carboxylase (Acacb) and Fatty acid Synthase (Fasn). Supplementation of old animals with LA did not reverse this necro-inflammatory phenotype, yet limited age-associated hepatic dyslipidemia. Dietary LA further affected a small but concerted number of hepatic genes regardless of age. These included declines in lipid and bile synthesis genes. Decline in lipid synthesis genes was further corroborated by a decrease in Fasn and Acc protein levels. Intriguingly, LA also altered the expression of genes governing circadian rhythm, most notably Bmal1, Npas2, and Per2, which changed in a coordinated manner with respect to their rhythmic transcription. Thus, advanced age is associated with a necro-inflammatory phenotype and increased lipid synthesis, while chronic LA supplementation influences hepatic genes associated with energy metabolism and circadian rhythm regardless of age.
2011-03-03 | GSE27625 | GEO
Project description:To determine the effects of age and lipoic acid supplementation on hepatic gene expression, we fed young (3 months) and old (24 months) male Fischer 344 rats a diet with or without 0.2% (w/w) R-?-lipoic acid (LA) for two weeks. Total RNA isolated from liver tissue was analyzed by Affymetrix microarray to examine changes in transcriptional profile. Results showed an increase in pro-inflammatory gene expression in the aging liver, with increased immune cell function and tissue remodeling genes, representing 45% of the age-related transcriptome changes. Increased inflammation was corroborated by increases in soluble ICAM1 levels with age. There were also observed age-related increases in transcription of genes related to lipid and cholesterol synthesis including Acetyl CoA Carboxylase (Acacb) and Fatty acid Synthase (Fasn). Supplementation of old animals with LA did not reverse this necro-inflammatory phenotype, yet limited age-associated hepatic dyslipidemia. Dietary LA further affected a small but concerted number of hepatic genes regardless of age. These included declines in lipid and bile synthesis genes. Decline in lipid synthesis genes was further corroborated by a decrease in Fasn and Acc protein levels. Intriguingly, LA also altered the expression of genes governing circadian rhythm, most notably Bmal1, Npas2, and Per2, which changed in a coordinated manner with respect to their rhythmic transcription. Thus, advanced age is associated with a necro-inflammatory phenotype and increased lipid synthesis, while chronic LA supplementation influences hepatic genes associated with energy metabolism and circadian rhythm regardless of age. Young (3 months) and old (24 months) Fischer 344 male rats were fed an AIN-93M diet ± 0.2% (w/w) R-?-lipoic acid for two weeks prior to sacrifice. Total RNA was extracted from the median lobe of the liver and analyzed using Affymetrix Rat Genome 230 2.0 Genechips. There were hybridizations for 8 animals in each of the young control, young LA-supplemented, and old control groups, and 6 animals in the old LA-supplemented group. There are only 6 animals in the old LA group because two animals died during the two-week feeding period. This is the reason for nonsequential numbering of animals in this group.
2011-03-03 | E-GEOD-27625 | biostudies-arrayexpress
Project description:Overnutrition disrupts circadian rhythms leading to dysregulated metabolism by mechanisms that are not well understood. Here we show that diet-induced obesity (DIO) causes massive remodeling of circadian enhancer activity and gene transcription in mouse liver. Remarkably, DIO triggers synchronous, high amplitude circadian rhythms of both fatty acid (FA) synthesis and oxidation. This gain of circadian rhythmicity in lipid metabolic pathways that oppose each other emphasizes the importance of balance and flux in normal hepatic lipid metabolism. DIO-promoted rhythmicity of Sterol Regulatory Element-Binding Protein (SREBP) activation, which was required not only for the induction of FA synthesis but also, surprisingly, for FA oxidation (FAO). DIO also brought about a high amplitude circadian rhythm of peroxisome proliferated receptor a (PPARa), which was required for FAO. Provision of a pharmacological ligand for PPARa abrogated the requirement of SREBP for FA oxidation (but not FA synthesis), suggesting that SREBP indirectly controls FA oxidation via production of an endogenous PPARa ligand. Moreover, the high amplitude circadian rhythm of PPARa imparts time-of-day-dependent responsiveness to lipid-lowering drugs. Thus, acquisition of rhythmicity for the non-core clock components PPARa and SREBP1 remodels metabolic gene transcription in response to a challenging nutritive environment and enables a chronopharmacological approach to metabolic disorders.
2018-07-26 | GSE108878 | GEO
Project description:The circadian rhythms of older individuals are normally shifted, and the metabolic functions of these individuals are degraded. How the link between metabolism and circadian rhythms is decoupled in peripheral metabolic organs with age increased is still largely unknown. Here, we analyze hepatic transcriptome in the liver at zeitgeber time (ZT) 1, 5, 9, 13, 17, 21 from C57BL/6J aged 2month, 6month and 12month. Transcriptional changes suggest that the peripheral circadian system is shifted and that the rhythmic lipid metabolism is disrupted in the liver with aging. Furthermore, we figure out liver EGR-1 might integrate the central and peripheral rhythms and regulate metabolic homeostasis in the liver. Another hepatic transcriptome of WT and Egr-1-KO liver samples at EGR-1 highest(H) and lowest(L) zeitgeber time in 2month, 6month and 12month were analyzed. The results indicated that the rhythmic coupling of EGR-1 and CIDEA regulates age-related metabolic dysfunction in the mouse liver.
2023-01-20 | GSE195456 | GEO
Project description:Disrupted sleep-wake and molecular circadian rhythms are a feature of aging associated with metabolic disease and reduced levels of NAD+, yet whether changes in nucleotide metabolism control circadian behavioral and genomic rhythms remains unknown. Here we reveal that supplementation with the NAD+ precursor nicotinamide riboside (NR) markedly reprograms metabolic and stress-response pathways that decline with aging through inhibition of the clock repressor PER2. NR enhances BMAL1 chromatin binding genome-wide through PER2K680 deacetylation, which in turn primes PER2 phosphorylation within a domain that controls nuclear transport and stability and which is mutated in human advanced sleep phase syndrome. In old mice, dampened BMAL1 chromatin binding, transcriptional oscillations, mitochondrial respiration rhythms, and late evening activity are restored by NAD+ repletion to youthful levels with NR. These results reveal effects of NAD+ on metabolism and the circadian system with aging through the spatiotemporal control of the molecular clock.
2020-05-04 | GSE133989 | GEO
Project description:Advances in circadian research revealed an intricate relationship between aging and circadian rhythms. However, whether and how the circadian machinery contribute to stem cell aging, especially in primates, remains poorly understood. In this study, we investigated the role of BMAL1, the only non-redundant circadian clock component, during aging in mesenchymal progenitor cells (MPCs). We observed an accelerated aging phenotype in both BMAL1 deficient human and cynomolgus monkey MPCs. Notably, this phenotype is mainly attributed to a transcriptional-independent role of BMAL1 in stabilizing the heterochromatin and thus preventing LINE1 activation. In senescent MPCs from human and cynomolgus monkeys, dampened LINE1 binding capacity of BMAL1 and synergistically activated LINE1 transcripts were observed. Furthermore, similar de-stabilized heterochromatin and aberrant LINE1s transcription was observed in the skin and muscle tissues from BMAL1-deficient cynomolgus monkey. Altogether, these findings uncover a noncanonical role of BMAL1 in stabilizing heterochromatin to inactivate LINE1 that drives aging in primates.
2022-03-18 | PXD030570 | Pride
Project description:Aging and age-related pathologies can be delayed by specifically targeting the senescence-associated secretory phenotype (SASP), a hallmark feature of senescent cells. Achieving the goal using small molecule inhibitors would have a tremendous impact on the quality of lifespan and burden of age-related chronic diseases. We report the potential of alpha lipoic acid (ALA), a naturally existing antioxidant, in targeting senescent cells via induction of programmed cell death. This study demonstrates the impact of alpha-lipoic acid as a medicinal compound on the expression profile of senescent cells and provides a strong rationale for its future use in geriatric medicine.
2022-12-31 | GSE156184 | GEO
Project description:The circadian clock generates daily rhythms in mammalian liver processes, such as glucose and lipid homeostasis, xenobiotic metabolism, and regeneration. The mechanisms governing these rhythms are not well understood, particularly the distinct contributions of the cell-autonomous clock and central pacemaker to rhythmic liver physiology. Through microarray expression profiling in MMH-D3 hepatocytes, we identified over 1,000 transcripts that exhibit circadian oscillations, demonstrating that many rhythms can be driven by the cell-autonomous clock and that MMH-D3 is a valid circadian model system. The genes represented by these circadian transcripts displayed both co-phasic and anti-phasic organization within a protein-protein interaction network, suggesting the existence of competition for binding sites or partners by genes of disparate transcriptional phases. Multiple pathways displayed enrichment in MMH-D3 circadian transcripts, including the polyamine synthesis module of the glutathione metabolic pathway. The polyamine synthesis module, which is highly associated with cell proliferation and whose products are required for initiation of liver regeneration, includes enzymes whose transcripts exhibit circadian oscillations, such as ornithine decarboxylase (Odc1) and spermidine synthase (Srm). Metabolic profiling revealed that the enzymatic product of SRM, spermidine, cycles as well. Thus, the cell-autonomous hepatocyte clock can drive a significant amount of transcriptional rhythms and orchestrate physiologically relevant modules such as polyamine synthesis.
2011-11-03 | GSE31049 | GEO
Project description:The circadian clock generates daily rhythms in mammalian liver processes, such as glucose and lipid homeostasis, xenobiotic metabolism, and regeneration. The mechanisms governing these rhythms are not well understood, particularly the distinct contributions of the cell-autonomous clock and central pacemaker to rhythmic liver physiology. Through microarray expression profiling in MMH-D3 hepatocytes, we identified over 1,000 transcripts that exhibit circadian oscillations, demonstrating that many rhythms can be driven by the cell-autonomous clock and that MMH-D3 is a valid circadian model system. The genes represented by these circadian transcripts displayed both co-phasic and anti-phasic organization within a protein-protein interaction network, suggesting the existence of competition for binding sites or partners by genes of disparate transcriptional phases. Multiple pathways displayed enrichment in MMH-D3 circadian transcripts, including the polyamine synthesis module of the glutathione metabolic pathway. The polyamine synthesis module, which is highly associated with cell proliferation and whose products are required for initiation of liver regeneration, includes enzymes whose transcripts exhibit circadian oscillations, such as ornithine decarboxylase (Odc1) and spermidine synthase (Srm). Metabolic profiling revealed that the enzymatic product of SRM, spermidine, cycles as well. Thus, the cell-autonomous hepatocyte clock can drive a significant amount of transcriptional rhythms and orchestrate physiologically relevant modules such as polyamine synthesis. Samples were collected every 2 hours for a duration of 46 hours from differentiated MMH-D3 hepatocytes synchronized via serum shock. Cells were synchronized by serum shock and incubated for 12 hours, and then samples were collected every 2 hours from 12 hours post-serum shock to 58 hours post-serum shock, for a total of 24 samples.
2011-11-03 | E-GEOD-31049 | biostudies-arrayexpress
Project description:Using RNA-seq, 39 cerebral cortex RNA samples were sequenced. The study design was as follows: Ad libitum fed rats at 6 months (n=3, 6 individuals pooled), 12 months (n=3, 6 individuals pooled) and 28 months (n=3, 6 individuals pooled). Calorie restricted rats at 6 months (n=3, 6 individuals pooled), 12 months (n=3, 6 individuals pooled) and 28 months (n=3, 6 individuals pooled). Rats fed alpha lipoic acid as a supplement to ad libitum at 12 months (n=3, 6 individuals pooled) and 28 months (n=3, 6 individuals pooled). Diet switching groups, where diet was changes at 12 months; 28 month ad libitum switched to calorie restriction (n=3, 6 individuals pooled), 28 month calorie restriction switched to ad libitum (n=3, 6 individuals pooled), 28 month ad libitum plus lipoic acid switched to calorie restriction (n=3, 6 individuals pooled), 28 month calorie restriction switched to ad libitum plus lipoic acid (n=3, 6 individuals pooled). Transcriptional profiling of the ageing cerebral cortex at 6, 12 and 28 months and the effect of diet on age and longevity, using carlorie restriction and alpha lipoic acid supplementation
2015-11-22 | E-GEOD-57110 | biostudies-arrayexpress