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Cardiac Transcriptome Analysis Reveals Nr4a1 Mediated Glucose Metabolism Dysregulation in Response to High-Fat Diet.

ABSTRACT: Obesity is associated with an increased risk of developing cardiovascular disease (CVD), with limited alterations in cardiac genomic characteristics known. Cardiac transcriptome analysis was conducted to profile gene signatures in high-fat diet (HFD)-induced obese mice. A total of 184 differentially expressed genes (DEGs) were identified between groups. Based on the gene ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs, the critical role of closely interlocked glucose metabolism was determined in HFD-induced cardiac remodeling DEGs, including Nr4a1, Fgf21, Slc2a3, Pck1, Gck, Hmgcs2, and Bpgm. Subsequently, the expression levels of these DEGs were evaluated in both the myocardium and palmitic acid (PA)-stimulated H9c2 cardiomyocytes using qPCR. Nr4a1 was highlighted according to its overexpression resulting from the HFD. Additionally, inhibition of Nr4a1 by siRNA reversed the PA-induced altered expression of glucose metabolism-related DEGs and hexokinase 2 (HK2), the rate-limiting enzyme in glycolysis, thus indicating that Nr4a1 could modulate glucose metabolism homeostasis by regulating the expression of key enzymes in glycolysis, which may subsequently influence cardiac function in obesity. Overall, we provide a comprehensive understanding of the myocardium transcript molecular framework influenced by HFD and propose Nr4a1 as a key glucose metabolism target in obesity-induced CVD.

SUBMITTER: Men L

PROVIDER: S-EPMC7397175 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Cardiac Transcriptome Analysis Reveals Nr4a1 Mediated Glucose Metabolism Dysregulation in Response to High-Fat Diet.

Men Lihui L Hui Wenting W Guan Xin X Song Tongtong T Wang Xuan X Zhang Siwei S Chen Xia X

Genes 20200629 7

Obesity is associated with an increased risk of developing cardiovascular disease (CVD), with limited alterations in cardiac genomic characteristics known. Cardiac transcriptome analysis was conducted to profile gene signatures in high-fat diet (HFD)-induced obese mice. A total of 184 differentially expressed genes (DEGs) were identified between groups. Based on the gene ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs, the crit ...[more]

PMID: 32610475

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Project description:Hu sheep and Tibetan sheep are two commonly raised local sheep breeds in China, and they have different morphological characteristics, such as tail type and adaptability to extreme environments. A fat tail in sheep is the main adipose depot in sheep, whereas the liver is an important organ for fat metabolism, with the uptake, esterification, oxidation, and secretion of fatty acids (FAs). Meanwhile, adaptations to high-altitude and arid environments also affect liver metabolism. Therefore, in this study, RNA-sequencing (RNA-seq) technology was used to characterize the difference in liver fat metabolism between Hu sheep and Tibetan sheep. We identified 1179 differentially expressed genes (DEGs) (Q-value < 0.05) between the two sheep breeds, including 25 fat-metabolism-related genes. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, 16 pathways were significantly enriched (Q-value < 0.05), such as the proteasome, glutamatergic synapse, and oxidative phosphorylation pathways. In particular, one of these pathways was enriched to be associated with fat metabolism, namely the thermogenesis pathway, to which fat-metabolism-related genes such as ACSL1, ACSL4, ACSL5, CPT1A, CPT1C, SLC25A20, and FGF21 were enriched. Then, the expression levels of ACSL1, CPT1A, and FGF21 were verified in mRNA and protein levels via qRT-PCR and Western blot analysis between the two sheep breeds. The results showed that the mRNA and protein expression levels of these three genes were higher in the livers of Tibetan sheep than those of Hu sheep. The above genes are mainly related to FAs oxidation, involved in regulating the oxidation of liver FAs. So, this study suggested that Tibetan sheep liver has a greater FAs oxidation level than Hu sheep liver. In addition, the significant enrichment of fat-metabolism-related genes in the thermogenesis pathway appears to be related to plateau-adaptive thermogenesis in Tibetan sheep, which may indicate that liver- and fat-metabolism-related genes have an impact on adaptive thermogenesis.

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Cardiac Transcriptome Analysis Reveals Nr4a1 Mediated Glucose Metabolism Dysregulation in Response to High-Fat Diet.

Publications

Cardiac Transcriptome Analysis Reveals Nr4a1 Mediated Glucose Metabolism Dysregulation in Response to High-Fat Diet.

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