7-Ketocholesterol Induces Lipid Metabolic Reprogramming and Enhances Cholesterol Ester Accumulation in Cardiac Cells

7-Ketocholesterol (7KCh) is a major oxidized cholesterol product abundant in lipoprotein deposits and atherosclerotic plaques. Our previous study has shown that 7KCh accumulates in erythrocytes of heart failure patients, and further investigation centered on how 7KCh may affect metabolism in cardiomyocytes. We applied metabolomics to study the metabolic changes in cardiac cell line HL-1 after treatment with 7KCh. Mevalonic acid (MVA) pathway-derived metabolites, such as farnesyl-pyrophosphate and geranylgeranyl-pyrophosphate, phospholipids, and triacylglycerols levels significantly declined, while the levels of lysophospholipids, such as lysophosphatidylcholines (lysoPCs) and lysophosphatidylethanolamines (lysoPEs), considerably increased in 7KCh-treated cells. Furthermore, the cholesterol content showed no significant change, but the production of cholesteryl esters was enhanced in the treated cells. To explore the possible mechanisms, we applied mRNA-sequencing (mRNA-seq) to study genes differentially expressed in 7KCh-treated cells. The transcriptomic analysis revealed that genes involved in lipid metabolic processes, including MVA biosynthesis and cholesterol transport and esterification, were differentially expressed in treated cells. Integrated analysis of both metabolomic and transcriptomic data suggests that 7KCh induces cholesteryl ester accumulation and reprogramming of lipid metabolism through altered transcription of such genes as sterol O-acyltransferase- and phospholipase A2-encoding genes. The 7KCh-induced reprogramming of lipid metabolism in cardiac cells may be implicated in the pathogenesis of cardiovascular diseases.

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Integrated Analysis of Liver Transcriptome, miRNA, and Proteome of Chinese Indigenous Breed Ningxiang Pig in Three Developmental Stages Uncovers Significant miRNA–mRNA–Protein Networks in Lipid Metabolism

Frontiers in Genetics ◽

10.3389/fgene.2021.709521 ◽

2021 ◽

Vol 12 ◽

Author(s):

Biao Li ◽

Jinzeng Yang ◽

Yan Gong ◽

Yu Xiao ◽

Qinghua Zeng ◽

...

Keyword(s):

Lipid Metabolism ◽

Expression Patterns ◽

Immune Defense ◽

Differentially Expressed ◽

Integrated Analysis ◽

Liver Development ◽

Liver Growth ◽

Functional Transformation ◽

Functional Changes ◽

Glycolipid Metabolism

Liver is an important metabolic organ of mammals. During each transitional period of life, liver metabolism is programmed by a complex molecular regulatory system for multiple physiological functions, many pathways of which are regulated by hormones and cytokines, nuclear receptors, and transcription factors. To gain a comprehensive and unbiased molecular understanding of liver growth and development in Ningxiang pigs, we analyzed the mRNA, microRNA (miRNA), and proteomes of the livers of Ningxiang pigs during lactation, nursery, and fattening periods. A total of 22,411 genes (19,653 known mRNAs and 2758 novel mRNAs), 1122 miRNAs (384 known miRNAs and 738 novel miRNAs), and 1123 unique proteins with medium and high abundance were identified by high-throughput sequencing and mass spectrometry. We show that the differences in transcriptional, post-transcriptional, or protein levels were readily identified by comparing different time periods, providing evidence that functional changes that may occur during liver development are widespread. In addition, we found many overlapping differentially expressed genes (DEGs)/differentially expressed miRNAs (DEMs)/differentially expressed proteins (DEPs) related to glycolipid metabolism in any group comparison. These overlapping DEGs/DEMs/DGPs may play an important role in functional transformation during liver development. Short Time-series Expression Miner (STEM) analysis revealed multiple expression patterns of mRNA, miRNA, and protein in the liver. Furthermore, several diverse key Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including immune defense, glycolipid metabolism, protein transport and uptake, and cell proliferation and development, were identified by combined analysis of DEGs and DGPs. A number of predicted miRNA–mRNA–protein pairs were found and validated by qRT-PCR and parallel reaction monitoring (PRM) assays. The results provide new and important information about the genetic breeding of Ningxiang pigs, which represents a foundation for further understanding the molecular regulatory mechanisms of dynamic development of liver tissue, functional transformation, and lipid metabolism.

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Multi-Omics Analysis of Fatty Acid Metabolism in Thyroid Carcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.737127 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jinghui Lu ◽

Yankun Zhang ◽

Min Sun ◽

Changyuan Ding ◽

Lei Zhang ◽

...

Keyword(s):

Thyroid Cancer ◽

Fatty Acid ◽

Lipid Metabolism ◽

Thyroid Carcinoma ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Metabolic Reprogramming ◽

Clinical Samples ◽

Integrated Analysis ◽

Additional Energy

ObjectivePapillary thyroid carcinoma (PTC) accounts for the majority of thyroid cancer and affects a large number of individuals. The pathogenesis of PTC has not been completely elucidated thus far. Metabolic reprogramming is a common feature in tumours. Our previous research revealed the reprogramming of lipid metabolism in PTC. Further studies on lipid metabolism reprogramming may help elucidate the pathogenesis of PTC.MethodsClinical samples of PTC and para-tumour tissue were analysed using lipidomic, proteomic, and metabolomic approaches. A multi-omics integrative strategy was adopted to identify the important pathways in PTC. The findings were further confirmed using western blotting, tissue microarray, bioinformatics, and cell migration assays.ResultsMulti-omics data and the results of integrated analysis revealed that the three steps of fatty acid metabolism (hydrolysis, transportation, and oxidation) were significantly enhanced in PTC. Especially, the expression levels of LPL, FATP2, and CPT1A, three key enzymes in the respective steps, were elevated in PTC. Moreover, LPL, FATP2 and CPT1A expression was associated with the TNM stage, lymph node metastasis of PTC. Moreover, high levels of FATP2 and CPT1A contributed to poor prognosis of PTC. In addition, ectopic overexpression of LPL, FATP2 and CPT1A can each promote the migration of thyroid cancer cells.ConclusionsOur data suggested that enhanced fatty acid metabolism supplied additional energy and substrates for PTC progression. This may help elucidating the underlying mechanism of PTC pathogenesis and identifying the potential therapeutic targets for PTC.

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Transcriptome Profile Analysis Reveals an Estrogen Induced LncRNA Associated with Lipid Metabolism and Carcass Traits in Chickens (Gallus Gallus)

Cellular Physiology and Biochemistry ◽

10.1159/000494785 ◽

2018 ◽

Vol 50 (5) ◽

pp. 1638-1658 ◽

Cited By ~ 6

Author(s):

Hong Li ◽

Zhenzhen Gu ◽

Liyu Yang ◽

Yadong Tian ◽

Xiangtao Kang ◽

...

Keyword(s):

Lipid Metabolism ◽

Target Genes ◽

Laying Hens ◽

Functional Enrichment ◽

Differentially Expressed ◽

Integrated Analysis ◽

Chicken Carcass ◽

Triglyceride Content

Background/Aims: Accumulating evidences have demonstrated that long noncoding RNAs (lncRNA) play important roles in hepatic lipid metabolism in mammals. However, no systematic screening of the potential lncRNAs in the livers of laying hens has been performed, and few studies have been reported concerning the effects of the lncRNAs on lipid metabolism in the livers of chickens during egg-laying period. The purpose of this study was to compare the difference in lncRNA expression in the livers of pre-laying and peak-laying hens at the age of 20 and 30 weeks old by transcriptome sequencing and to investigate the interaction networks among lncRNAs, mRNAs and miRNAs. Moreover, the regulatory mechanism and biological function of lncLTR, a significantly differentially expressed lncRNA in the liver between pre- and peak-laying hens, was explored in vitro and in vivo. Methods: Bioinformatics analyses were conducted to identify the differentially expressed (DE) lncRNAs between the two groups of hens. The target genes of the DE lncRNA were predicated for further functional enrichment. An integrated analysis was performed among the DE lncRNA datasets, DE mRNAs and DE miRNA datasets obtained from the same samples to predict the interaction relationship. In addition, in vivo and in vitro trials were carried out to determine the expression regulation of lncLTR, and polymorphism association analysis was conducted to detect the biological role of ncLTR. Results: A total of 124 DE lncRNAs with a P-value ≤ 0.05 were identified. Among them, 44 lncRNAs including 30 known and 14 novel lncRNAs were significant differentially expressed (SDE) with FDR ≤ 0.05. Thirty-two lncRNAs were upregulated and 12 were downregulated in peak-laying group compared with pre-laying group. The functional enrichment results revealed that target genes of some lncRNAs are involved in the lipid metabolism process. Integrated analysis suggested that some of the genes involved in lipid metabolism might be regulated by both the lncRNA and the miRNA. In addition, an upregulated lncRNA, designated lncLTR, was demonstrated to be induced by estrogen via ERβ signaling. The c242. G>A SNP in lncLTR was significantly associated with chicken carcass weight, evisceration weight, semi-evisceration weight, head weight, double-wing weight, claw weight traits, and blood biochemical index, especially for the blood triglyceride content. Conclusion: A series of lncRNAs associated with lipid metabolism in the livers of chickens were identified by transcriptome sequencing and functional analysis, providing a valuable data resource for further studies on chicken hepatic metabolism activities. LncLTR was regulated by estrogen via ERβ signaling and associated with chicken carcass trait and blood triglyceride content.

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Genome Scale-Differential Flux Analysis reveals deregulation of lung cell metabolism on SARS-CoV-2 infection

PLoS Computational Biology ◽

10.1371/journal.pcbi.1008860 ◽

2021 ◽

Vol 17 (4) ◽

pp. e1008860

Author(s):

Piyush Nanda ◽

Amit Ghosh

Keyword(s):

Lipid Metabolism ◽

Metabolic Reprogramming ◽

Host Cells ◽

Integrated Analysis ◽

Virus Protein ◽

Acid Oxidation ◽

Flux Analysis ◽

Context Specific ◽

Genome Scale ◽

Differential Flux

The COVID-19 pandemic is posing an unprecedented threat to the whole world. In this regard, it is absolutely imperative to understand the mechanism of metabolic reprogramming of host human cells by SARS-CoV-2. A better understanding of the metabolic alterations would aid in design of better therapeutics to deal with COVID-19 pandemic. We developed an integrated genome-scale metabolic model of normal human bronchial epithelial cells (NHBE) infected with SARS-CoV-2 using gene-expression and macromolecular make-up of the virus. The reconstructed model predicts growth rates of the virus in high agreement with the experimental measured values. Furthermore, we report a method for conducting genome-scale differential flux analysis (GS-DFA) in context-specific metabolic models. We apply the method to the context-specific model and identify severely affected metabolic modules predominantly comprising of lipid metabolism. We conduct an integrated analysis of the flux-altered reactions, host-virus protein-protein interaction network and phospho-proteomics data to understand the mechanism of flux alteration in host cells. We show that several enzymes driving the altered reactions inferred by our method to be directly interacting with viral proteins and also undergoing differential phosphorylation under diseased state. In case of SARS-CoV-2 infection, lipid metabolism particularly fatty acid oxidation, cholesterol biosynthesis and beta-oxidation cycle along with arachidonic acid metabolism are predicted to be most affected which confirms with clinical metabolomics studies. GS-DFA can be applied to existing repertoire of high-throughput proteomic or transcriptomic data in diseased condition to understand metabolic deregulation at the level of flux.

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Genome Scale-Differential Flux Analysis reveals deregulation of lung cell metabolism on SARS Cov2 infection

10.1101/2020.11.29.402404 ◽

2020 ◽

Author(s):

Piyush Nanda ◽

Amit Ghosh

Keyword(s):

Lipid Metabolism ◽

Metabolic Reprogramming ◽

Host Cells ◽

Integrated Analysis ◽

Virus Protein ◽

Acid Oxidation ◽

Flux Analysis ◽

Context Specific ◽

Genome Scale ◽

Differential Flux

AbstractThe COVID-19 pandemic is posing an unprecedented threat to the whole world. In this regard, it is absolutely imperative to understand the mechanism of metabolic reprogramming of host human cells by SARS Cov2. A better understanding of the metabolic alterations would aid in design of better therapeutics to deal with COVID-19 pandemic. We developed an integrated genome-scale metabolic model of normal human bronchial epithelial cells (NHBE) infected with SARS Cov2 using gene-expression and macromolecular make-up of the virus. The reconstructed model predicts growth rates of the virus in high agreement with the experimental measured values. Furthermore, we report a method for conducting genome-scale differential flux analysis (GS-DFA) in context-specific metabolic models. We apply the method to the context-specific model and identify severely affected metabolic modules predominantly comprising of lipid metabolism. We conduct an integrated analysis of the flux-altered reactions, host-virus protein-protein interaction network and phospho-proteomics data to understand the mechanism of flux alteration in host cells. We show that several enzymes driving the altered reactions inferred by our method to be directly interacting with viral proteins and also undergoing differential phosphorylation under diseased state. In case of SARS Cov2 infection, lipid metabolism particularly fatty acid oxidation and beta-oxidation cycle along with arachidonic acid metabolism are predicted to be most affected which confirms with clinical metabolomics studies. GS-DFA can be applied to existing repertoire of high-throughput proteomic or transcriptomic data in diseased condition to understand metabolic deregulation at the level of flux.

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Integrated Proteomics and Metabolomics Analysis of Perirenal Adipose Tissue in Obese Rabbits Treated with a Restricted Diet

Biology ◽

10.3390/biology10040321 ◽

2021 ◽

Vol 10 (4) ◽

pp. 321

Author(s):

Jiahao Shao ◽

Ting Pan ◽

Jie Wang ◽

Tao Tang ◽

Yanhong Li ◽

...

Keyword(s):

Weight Loss ◽

Lithocholic Acid ◽

Mevalonic Acid ◽

Differentially Expressed ◽

Integrated Analysis ◽

Rapid Weight Loss ◽

Increased Risk ◽

Weight Loss Behavior ◽

Treatment Of Obesity ◽

Metabolomics Analysis

In recent years, many people have shown an excess of fat accumulation. Known as obesity, this lesion poses an increased risk for multiple diseases, such as endocrine disease, diabetes, and cancer, and has reached epidemic proportions. Accompanied by the development of obesity, concern over body image and weight loss behavior is a growing social problem and public health threat, causing concern for many health professionals. However, the consequences of rapid weight loss remain largely unclear. Here, we applied an integrated proteomics and metabolomics analysis to investigate the effects of dieting on the proteins and metabolites in obese rabbits. Our study revealed that 343 differentially expressed proteins (136 upregulated and 207 downregulated) and 150 differentially expressed metabolites (91 upregulated and 59 downregulated) were identified. These molecules are mainly involved in the biological processes, including amino acid metabolism, lipid metabolism, and membrane and cytoskeleton reconstruction. The integrated analysis found that mevalonic acid, arachidonic acid, 15(S)-HpETE, cholecalciferol, hydrocortisone, lipoxin B4, lithocholic acid, etc. were associated with multiple pathways, and they may be the key factors to fight inflammation induced by a high-fat diet (HFD). Overall, this study provides further insight into the consequences of dieting-mediated weight loss and may contribute to the prevention and treatment of obesity.

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Characterization of Differentially Expressed Circulating miRNAs in Metabolically Healthy versus Unhealthy Obesity

Biomedicines ◽

10.3390/biomedicines9030321 ◽

2021 ◽

Vol 9 (3) ◽

pp. 321

Author(s):

Susana Rovira-Llopis ◽

Rubén Díaz-Rúa ◽

Carmen Grau-del Valle ◽

Francesca Iannantuoni ◽

Zaida Abad-Jimenez ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Metabolism ◽

Insulin Signalling ◽

Cross Sectional Study ◽

Differentially Expressed ◽

Circulating Mirnas ◽

Oxidative Stress Biomarkers ◽

Cross Sectional ◽

Metabolically Healthy Obese ◽

Metabolically Healthy

Obese individuals without metabolic comorbidities are categorized as metabolically healthy obese (MHO). MicroRNAs (miRNAs) may be implicated in MHO. This cross-sectional study explores the link between circulating miRNAs and the main components of metabolic syndrome (MetS) in the context of obesity. We also examine oxidative stress biomarkers in MHO vs. metabolically unhealthy obesity (MUO). We analysed 3536 serum miRNAs in 20 middle-aged obese individuals: 10 MHO and 10 MUO. A total of 159 miRNAs were differentially expressed, of which, 72 miRNAs (45.2%) were higher and 87 miRNAs (54.7%) were lower in the MUO group. In addition, miRNAs related to insulin signalling and lipid metabolism pathways were upregulated in the MUO group. Among these miRNAs, hsa-miR-6796-5p and hsa-miR-4697-3p, which regulate oxidative stress, showed significant correlations with glucose, triglycerides, HbA1c and HDLc. Our results provide evidence of a pattern of differentially expressed miRNAs in obesity according to MetS, and identify those related to insulin resistance and lipid metabolism pathways.

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Integrated analysis of lncRNA, miRNA and mRNA profiles reveals potential lncRNA functions during early HIV infection

Journal of Translational Medicine ◽

10.1186/s12967-021-02802-9 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Lianwei Ma ◽

Hui Zhang ◽

Yue Zhang ◽

Hailong Li ◽

Minghui An ◽

...

Keyword(s):

Hiv Infection ◽

Immune Activation ◽

Expression Profiles ◽

Critical Role ◽

Differentially Expressed ◽

Integrated Analysis ◽

Target Mrnas ◽

Immunodeficiency Virus ◽

Mirna Sequencing ◽

Hiv 1

Abstract Background Long noncoding RNAs (lncRNAs) can regulate gene expression in a cis-regulatory fashion or as “microRNA sponges”. However, the expression and functions of lncRNAs during early human immunodeficiency virus (HIV) infection (EHI) remain unclear. Methods 3 HAART-naive EHI patients and 3 healthy controls (HCs) were recruited in this study to perform RNA sequencing and microRNA (miRNA) sequencing. The expression profiles of lncRNAs, mRNAs and miRNAs were obtained, and the potential roles of lncRNAs were analysed based on discovering lncRNA cis-regulatory target mRNAs and constructing lncRNA–miRNA–mRNA competing endogenous RNA (ceRNA) networks. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on 175 lncRNA-associated differentially expressed (DE) mRNAs to investigate the potential functions of DE lncRNAs in ceRNA networks. Results A total of 242 lncRNAs, 1240 mRNAs and 21 mature known miRNAs were determined as differentially expressed genes in HAART-naive EHI patients compared to HCs. Among DE lncRNAs, 44 lncRNAs were predicted to overlap with 41 target mRNAs, and 107 lncRNAs might regulate their nearby DE mRNAs. Two DE lncRNAs might regulate their cis-regulatory target mRNAs BTLA and ZAP70, respectively, which were associated with immune activation. In addition, the ceRNA networks comprised 160 DE lncRNAs, 21 DE miRNAs and 175 DE mRNAs. Seventeen DE lncRNAs were predicted to regulate HIF1A and TCF7L2, which are involved in the process of HIV-1 replication. Twenty DE lncRNAs might share miRNA response elements (MREs) with FOS, FOSB and JUN, which are associated with both immune activation and HIV-1 replication. Conclusions This study revealed that lncRNAs might play a critical role in HIV-1 replication and immune activation during EHI. These novel findings are helpful for understanding of the pathogenesis of HIV infection and provide new insights into antiviral therapy.

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High-throughput screening of circRNAs reveals novel mechanisms of tuberous sclerosis complex-related renal angiomyolipoma

Human Genomics ◽

10.1186/s40246-021-00344-1 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Yang Zhao ◽

Hao Guo ◽

Wenda Wang ◽

Guoyang Zheng ◽

Zhan Wang ◽

...

Keyword(s):

Lipid Metabolism ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Regulatory Network ◽

High Throughput Screening ◽

Kidney Tissue ◽

Cell Types ◽

The Body ◽

Differentially Expressed ◽

Renal Angiomyolipoma

Abstract Objective Tuberous sclerosis complex (TSC) is a rare autosomal dominant disease characterized by lesions throughout the body. Our previous study showed the abnormal up-regulation of miRNAs plays an important part in the pathogenesis of TSC-related renal angiomyolipoma (TSC-RAML). circRNAs were known as important regulators of miRNA, but little is known about the circRNAs in TSC-RAMLs. Methods Microarray chips and RNA sequencing were used to identify the circRNAs and mRNAs that were differently expressed between the TSC-RAML and normal kidney tissue. A competitive endogenous RNA (ceRNA) regulatory network was constructed to reveal the regulation of miRNAs and mRNAs by the circRNAs. The biological functions of circRNA and mRNA were analyzed by pathway analysis. Microenvironmental cell types were estimated with the MCP-counter package. Results We identified 491 differentially expressed circRNAs (DECs) and 212 differentially expressed genes (DEGs), and 6 DECs were further confirmed by q-PCR. A ceRNA regulatory network which included 6 DECs, 5 miRNAs, and 63 mRNAs was established. Lipid biosynthetic process was significantly up-regulated in TSC-RAML, and the humoral immune response and the leukocyte chemotaxis pathway were found to be down-regulated. Fibroblasts are enriched in TSC-RAML, and the up-regulation of circRNA_000799 and circRNA_025332 may be significantly correlated to the infiltration of the fibroblasts. Conclusion circRNAs may regulate the lipid metabolism of TSC-RAML by regulation of the miRNAs. Fibroblasts are enriched in TSC-RAMLs, and the population of fibroblast may be related to the alteration of circRNAs of TSC-RAML. Lipid metabolism in fibroblasts is a potential treatment target for TSC-RAML.

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Comprehensive Analysis of Transcriptome and Metabolome Reveals the Flavonoid Metabolic Pathway Is Associated with Fruit Peel Coloration of Melon

Molecules ◽

10.3390/molecules26092830 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2830

Author(s):

Aiai Zhang ◽

Jing Zheng ◽

Xuemiao Chen ◽

Xueyin Shi ◽

Huaisong Wang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Comprehensive Analysis ◽

Differentially Expressed ◽

Integrated Analysis ◽

Fruit Peel ◽

External Quality ◽

Color Formation ◽

Peel Color ◽

Dark Green

The peel color is an important external quality of melon fruit. To explore the mechanisms of melon peel color formation, we performed an integrated analysis of transcriptome and metabolome with three different fruit peel samples (grey-green ‘W’, dark-green ‘B’, and yellow ‘H’). A total of 40 differentially expressed flavonoids were identified. Integrated transcriptomic and metabolomic analyses revealed that flavonoid biosynthesis was associated with the fruit peel coloration of melon. Twelve differentially expressed genes regulated flavonoids synthesis. Among them, nine (two 4CL, F3H, three F3′H, IFS, FNS, and FLS) up-regulated genes were involved in the accumulation of flavones, flavanones, flavonols, and isoflavones, and three (2 ANS and UFGT) down-regulated genes were involved in the accumulation of anthocyanins. This study laid a foundation to understand the molecular mechanisms of melon peel coloration by exploring valuable genes and metabolites.

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