Aging and Obesity Induce Distinct Gene Expression Adaptation in the Liver of C57BL/6J Mice

Capel, Frédéric; Delmotte, M.H.; Brun, Marion; Lonchampt, Michel; Fanti, Brant de; Xuereb, Laura; Baschet, Louise; Rolland, Gaëlle; Galizzi, Jean‐Pierre; Lockhart, Brian P.; Ktorza, Alain; Dacquet, Catherine

doi:10.1159/000328190

Cited by 8 publications

(11 citation statements)

References 55 publications

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“…The decreases in abundance of ACC and FAS found in this study are consistent with published reports where mRNA levels of ACC and FAS, and FAS protein abundance were decreased after high fat diet feeding [10,20,21]. However, the reports, where SCD-1 mRNA was shown to be increased upon high fat diet feeding [11,18], are inconsistent with our results and illustrate the importance of assessing protein abundance changes. Another lipogenic enzyme, ATP-citrate synthase (aka ATP-citrate lyase, ACL), was decreased in abundance in liver due to high fat feeding, which is also consistent with published data [21].…”

Section: Discussionsupporting

confidence: 83%

“…Gene expression changes in insulin resistant liver have been investigated by microarray analysis and Real Time RT-PCR, using the high fat diet-induced model of insulin resistance in mice, Several genes, such as fatty acid synthase (FAS), Acetyl-CoA carboxylase (ACC) and stearoyl CoA desaturase (SCD) were highlighted [10,11]. Other genes involved in metabolism, transcription, signaling and defense/ inflammation mechanism have also been studied by analyzing changes in mRNA expression [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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High Fat Diet-Induced Changes in Hepatic Protein Abundance in Mice

Luo

Mengos

Stubblefield

et al. 2012

jpb

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Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, type 2 diabetes, and dyslipidemia. The purpose of this study was to identify novel proteins and pathways that contribute to the pathogenesis and complications of NAFLD. C57BL/6J male mice were fed a 60% (HFD) or 10% (LFD) high or low fat diet. HFD induced obesity, hepatic steatosis and insulin resistance (euglycemic clamps, glucose infusion rate: LFD 50.5 ± 6.4 vs. HFD 14.2 ± 9.5 μg/ (g·min); n = 12). Liver proteins were analyzed by mass spectrometry-based proteomics analysis. Numerous hepatic proteins were altered in abundance after 60% HFD feeding. Nine down-regulated and nine up-regulated proteins were selected from this list for detailed analysis based on the criteria of 1.5-fold difference, consistency across replicates, and having at least 2 spectra assigned. Proteins that decreased in abundance were acyl-coA desaturase-I (SCD-1), acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), pyruvate kinase isozymes R/L (PKLR), NADP-dependent malic enzyme (ME-1), ATP-citrate synthase (ACL), ketohexokinase (KHK), long-chain-fatty acid-CoA ligase-5 (ACSL-5) and carbamoyl-phosphate synthase-I (CPS-1). Those that increased were KIAA0564, apolipoprotein A-I (apoA-1), ornithine aminotransferase (OAT), multidrug resistance protein 2 (MRP-2), liver carboxylesterase-I (CES-1), aminopeptidase N (APN), fatty aldehyde dehydrogenase (FALDH), major urinary protein 2 (MUP-2) and KIAA0664. KIAA0564 and KIAA0664 proteins are uncharacterized and are novel proteins associated with NAFLD. The decreased abundance of normally highly abundant proteins like FAS and CPS-1 was confirmed by Coomassie Blue staining after bands were identified by MS/MS, and immunoblot analysis confirmed the increased abundance of KIAA0664 after 60% HFD feeding. In conclusion, this study shows NAFLD is characterized by changes in abundance of proteins related to cell injury, inflammation, and lipid metabolism. Two novel and uncharacterized proteins, KIAA0564 and KIAA0664, may provide insight into the pathogenesis of NAFLD induced by lipid oversupply.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

High Fat Diet-Induced Changes in Hepatic Protein Abundance in Mice

Luo

Mengos

Stubblefield

et al. 2012

jpb

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“…Due to a transcriptional coactivator activity, lipin1 amplified the stimulatory effect of Pgc1α and Pparα on the expression of genes involved in hepatic fatty acid oxidation [28]. We previously found that Pgc1α mRNA expression was repressed with aging in the mouse liver [14]. Hence, the downregulation of Lipin1 and Pgc1α expression in the liver of 12-month-old mice suggests a defective fatty acid oxidative ability and reinforces the crucial role of Pgc1α in the aging process.…”

Section: Discussionmentioning

confidence: 90%

“…In the liver, SREBP-1c is encoded by the Srebf1 gene driving lipogenesis in response to insulin [9,10] and cooperating frequently with other factors [11,12,13]. We recently confirmed that SREBP-1c may play a central regulatory role during a short- and a long-term high-fat diet (HFD)-induced obesity and insulin resistance in mice [14]. …”

Section: Introductionmentioning

confidence: 99%

Analysis of Sterol-Regulatory Element-Binding Protein 1c Target Genes in Mouse Liver during Aging and High-Fat Diet

Capel

Rolland-Valognes²,

Dacquet³

et al. 2013

Lifestyle Genomics

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Background: The sterol regulatory element-binding protein (SREBP) 1c contributes to the transcriptional coordination of cholesterol, fatty acid, and carbohydrate metabolisms. Alterations in these processes accelerate the progression of hepatic steatosis and insulin resistance during aging and obesity. Methods: Using an ex vivo chromatin immunoprecipitation coupled to microarray (ChIP-on-chip) technique combined with genome-wide gene expression analysis, we analyzed the transcriptomic adaptations mediated by Srebp-1c binding to gene promoters in the liver of mice fed with a low-fat diet or a high-fat diet (HFD) for either 1 or 12 months. Results: Aging had a higher transcriptional impact than HFD and modified the expression of genes involved in fatty acid oxidation and oxidative stress. HFD was associated with a marked induction of genes involved in lipid and cholesterol metabolism. The prolonged high-fat feeding together with the aging effects stimulates inflammatory pathways. ChIP-on-chip applied to aging and HFD analyses revealed that the binding of SREBP-1c to a series of promoters accompanied a paralleled modification of gene expression. Therefore, SREBP-1c could play a role in aging and high-fat feeding through the regulation of genes involved in lipid metabolism and inflammatory response. Conclusions: This study represents an original ex vivo experiment to elucidate the molecular events involved in metabolic disorders.

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“…The global methylation status in lipid-accumulated mouse primary hepatocytes by ChIP-on-chip analysis showed that hepatic lipid accumulation induced aberrant H3K9me3 and H3K4me3 status in peroxisome proliferator-activated receptor alpha and hepatic lipid catabolism network genes, reducing their mRNA expression compared with nontreated control hepatocytes [85]. Aging is also an important variable since hepatic gene expression changes were more pronounced in the context of aged C57BL/6J mice [86], and the molecular mechanisms underlying high-fat feeding or aging which mediated insulin resistance were not identical. …”

Section: Effect Of Dietary Fat Contentmentioning

confidence: 99%

The Use of Transcriptomics to Unveil the Role of Nutrients in Mammalian Liver

Osada

2013

ISRN Nutrition

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Liver is the organ primarily responding to diet, and it is crucial in determining plasma carbohydrate, protein, and lipid levels. In addition, it is mainly responsible for transformation of xenobiotics. For these reasons, it has been a target of transcriptomic analyses. In this review, we have covered the works dealing with the response of mammalian liver to different nutritional stimuli such as fasting/feeding, caloric restriction, dietary carbohydrate, cholesterol, fat, protein, bile acid, salt, vitamin, and oligoelement contents. Quality of fats or proteins has been equally addressed, and has the influence of minor dietary components. Other compounds, not purely nutritional as those represented by alcohol and food additives, have been included due to their relevance in processed food. The influence has been studied not only on mRNA but also on miRNA. The wide scope of the technology clearly reflects that any simple intervention has profound changes in many metabolic parameters and that there is a synergy in response when more compounds are included in the intervention. Standardized arrays to systematically test the same genes in all studies and analyzing data to establish patterns of response are required, particularly for RNA sequencing. Moreover, RNA is a valuable, easy-screening ally but always requires further confirmation.

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Aging and Obesity Induce Distinct Gene Expression Adaptation in the Liver of C57BL/6J Mice

Cited by 8 publications

References 55 publications

High Fat Diet-Induced Changes in Hepatic Protein Abundance in Mice

High Fat Diet-Induced Changes in Hepatic Protein Abundance in Mice

Analysis of Sterol-Regulatory Element-Binding Protein 1c Target Genes in Mouse Liver during Aging and High-Fat Diet

The Use of Transcriptomics to Unveil the Role of Nutrients in Mammalian Liver

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