STARD1 Functions in Mitochondrial Cholesterol Metabolism and Nascent HDL Formation. Gene Expression and Molecular mRNA Imaging Show Novel Splicing and a 1:1 Mitochondrial Association

Abstract Background Genes that belong to the same network are frequently co-expressed, but collectively, how the coordination of the whole transcriptome is perturbed during aging remains unclear. To explore this, we calculated the correlation of each gene in the transcriptome with every other, in the brain of young and older outbred deer mice (P. leucopus and P. maniculatus). Results In about 25 % of the genes, coordination was inversed during aging. Gene Ontology analysis in both species, for the genes that exhibited inverse transcriptomic coordination during aging pointed to alterations in the perception of smell, a known impairment occurring during aging. In P. leucopus, alterations in genes related to cholesterol metabolism were also identified. Among the genes that exhibited the most pronounced inversion in their coordination profiles during aging was THBS4, that encodes for thrombospondin-4, a protein that was recently identified as rejuvenation factor in mice. Relatively to its breadth, abolishment of coordination was more prominent in the long-living P. leucopus than in P. maniculatus but in the latter, the intensity of de-coordination was higher. Conclusions There sults suggest that aging is associated with more stringent retention of expression profiles for some genes and more abrupt changes in others, while more subtle but widespread changes in gene expression appear protective. Our findings shed light in the mode of the transcriptional changes occurring in the brain during aging and suggest that strategies aiming to broader but more modest changes in gene expression may be preferrable to correct aging-associated deregulation in gene expression.

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Abstract 162: Cholesterol metabolism gene expression and prostate cancer-specific outcomes in radiotherapy-treated patients

10.1158/1538-7445.am2021-162 ◽

2021 ◽

Author(s):

Sarah J. Winter ◽

Sophia Halliday ◽

Konrad H. Stopsack ◽

Sarah O. Osman ◽

Alan R. Hounsell ◽

...

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Cholesterol Metabolism ◽

Metabolism Gene

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Human Lupus Plasma Pro-Atherogenic Effects on Cultured Macrophages Are Not Mitigated by Statin Therapy: A Mechanistic LAPS Substudy

Medicina ◽

10.3390/medicina55090514 ◽

2019 ◽

Vol 55 (9) ◽

pp. 514 ◽

Cited By ~ 1

Author(s):

Reiss ◽

Arain ◽

Kasselman ◽

Renna ◽

Zhen ◽

...

Keyword(s):

Gene Expression ◽

Lupus Erythematosus ◽

Cholesterol Metabolism ◽

Lipid Lowering ◽

Cholesterol Transport ◽

Atp Binding ◽

Peroxisome Proliferator ◽

Atherosclerotic Cardiovascular Disease ◽

Peroxisome Proliferator Activated Receptor ◽

Atp Binding Cassette

Background and Objectives: Atherosclerotic cardiovascular disease (CVD) remains a major cause of morbidity and mortality in persons with systemic lupus erythematosus (SLE, lupus). Atherosclerosis, which involves interplay between cholesterol metabolism and cellular inflammatory pathways, is primarily treated with statins since statins have lipid-lowering and anti-inflammatory properties. The Lupus Atherosclerosis Prevention Study (LAPS) was designed to investigate the efficacy of statins against CVD in SLE patients. LAPS demonstrated that 2 years of atorvastatin administration did not reduce atherosclerosis progression in lupus patients. In this LAPs substudy, we use cultured macrophages to explore the atherogenic properties of plasma from LAPS subjects to explain the mechanistic rationale for the inability of statins to reduce CVD in lupus. Materials and Methods: THP-1 differentiated macrophages were treated for 18 h with 10% SLE patient plasma obtained pre- and post-atorvastatin therapy or placebo. Gene expression of the following cholesterol transport genes was measured by qRT-PCR. For efflux—ATP binding cassette transporter (ABC)A1 and ABCG1, 27-hydroxylase, peroxisome proliferator-activated receptor (PPAR)γ, and liver X receptor (LXR)α; and for influx—cluster of differentiation 36 (CD36) and scavenger receptor (ScR)A1. Results: Macrophages exposed to plasma from both statin-treated and placebo-treated groups showed a significant decrease in cholesterol efflux proteins ATP binding cassette (ABC) transporters A1 and ABCG1, an increase in 27-hydroxylase, an increase in the LDL receptor and a decrease in intracellular free cholesterol. No change in influx receptors ScRA1 and CD36, nor nuclear proteins LXRα and PPARγ was observed. Conclusions: Statins do not normalize pro-atherogenic changes induced by lupus and these changes continue to worsen over time. This study provides mechanistic insight into LAPS findings by demonstrating that statins are overall ineffective in altering the balance of cholesterol transport gene expression in human macrophages. Furthermore, our study suggests that statins as a CVD treatment may not be useful in attenuating lipid overload in the SLE environment.

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Recipient perioperative cholesterolaemia and graft cholesterol metabolism gene expression predict liver transplant outcome

Liver International ◽

10.1111/liv.12351 ◽

2013 ◽

Vol 34 (7) ◽

pp. e290-e301 ◽

Cited By ~ 3

Author(s):

Stefano Ginanni Corradini ◽

Maria Siciliano ◽

Lucia Parlati ◽

Antonio Molinaro ◽

Alfredo Cantafora ◽

...

Keyword(s):

Gene Expression ◽

Liver Transplant ◽

Cholesterol Metabolism ◽

Transplant Outcome ◽

Metabolism Gene

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Gene-environment interactions reveal a homeostatic role for cholesterol metabolism during dietary folate perturbation in mice

Physiological Genomics ◽

10.1152/physiolgenomics.00294.2007 ◽

2008 ◽

Vol 35 (2) ◽

pp. 182-190 ◽

Cited By ~ 9

Author(s):

Toshimori Kitami ◽

Renee Rubio ◽

William O'Brien ◽

John Quackenbush ◽

Joseph H. Nadeau

Keyword(s):

Gene Expression ◽

Total Cholesterol ◽

Birth Defects ◽

Metabolic Pathways ◽

Cholesterol Metabolism ◽

Cholesterol Biosynthesis ◽

Inbred Strains ◽

Serum Folate ◽

Folate Supplementation ◽

Dietary Folate

Dietary folate supplementation can dramatically reduce the severity and incidence of several common birth defects and adult diseases that are associated with anomalies in homocysteine and folate metabolism. The common polymorphisms that adversely affect these metabolic pathways do not fully account for the particular birth defects and adult diseases that occur in at-risk individuals. To test involvement of folate, homocysteine, and other pathways in disease pathogenesis and treatment response, we analyzed global and pathway-specific changes in gene expression and levels of selected metabolites after depletion and repletion of dietary folate in two genetically distinct inbred strains of mice. Compared with the C57BL/6J strain, A/J showed greater homeostatic response to folate perturbation by retaining a higher serum folate level and minimizing global gene expression changes. Remarkably, folate perturbation led to systematic strain-specific differences only in the expression profile of the cholesterol biosynthesis pathway and to changes in levels of serum and liver total cholesterol. By genetically increasing serum and liver total cholesterol levels in APOE-deficient mice, we modestly but significantly improved folate retention during folate depletion, suggesting that homeostasis among the homocysteine, folate and cholesterol metabolic pathways contributes to the beneficial effects of dietary folate supplementation.

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Pancreatic β-Cell Dysfunction in Diet-Induced Obese Mice: Roles of AMP-Kinase, Protein Kinase Cε, Mitochondrial and Cholesterol Metabolism, and Alterations in Gene Expression

PLoS ONE ◽

10.1371/journal.pone.0153017 ◽

2016 ◽

Vol 11 (4) ◽

pp. e0153017 ◽

Cited By ~ 14

Author(s):

Émilie Pepin ◽

Anfal Al-Mass ◽

Camille Attané ◽

Kezhuo Zhang ◽

Julien Lamontagne ◽

...

Keyword(s):

Gene Expression ◽

Protein Kinase ◽

Cholesterol Metabolism ◽

Pancreatic Β Cell ◽

Obese Mice ◽

Amp Kinase ◽

Β Cell ◽

Cell Dysfunction

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ATF3 and EGR2 gene expression levels in sdLDL-treated macrophages of patients with coronary artery stenosis

LaboratoriumsMedizin ◽

10.1515/labmed-2017-0138 ◽

2018 ◽

Vol 42 (1-2) ◽

pp. 23-29

Author(s):

Sayed R. Hosseini-Fard ◽

Mohsen Khosravi ◽

Amaneh Yarnazari ◽

Parisa Hassanpour ◽

Abdollah Amirfarhangi ◽

...

Keyword(s):

Gene Expression ◽

Coronary Artery ◽

Cholesterol Metabolism ◽

Quantitative Polymerase Chain Reaction ◽

Fold Change ◽

Expression Level ◽

Control Group ◽

Expression Levels ◽

Vessel Disease ◽

Gene Expression Levels

AbstractBackground:The metabolism of cholesteryl esters (CEs) is under the control of a gene network in macrophages. Several genes such asATF3andEGR2are related to cholesterol metabolism.Methods:In this study, theATF3andEGR2gene expression levels were evaluated in differentiated macrophages of subjects undergoing coronary artery angiography [controls (<5% stenosis), patients (>70% stenosis)] after treatment with small dense low density lipoprotein (sdLDL) particles. Monocytes were isolated using a RosetteSep Kit and were differentiated into macrophages using the M-CSF factor. A modified heparin-MgSO4-PEG method was used for the sdLDL preparation. TheATF3andEGR2gene expression levels were measured by the real-time quantitative polymerase chain reaction (RT-qPCR) technique.Results:In contrast with the control group (p=0.4), theATF3expression level reduced significantly in the differentiated macrophages from all patients [single vessel disease (SVD), fold change 17 times, p=0.02; two vessel disease (2VD), fold change 1.5 times, p=0.05; three vessel disease (3VD), fold change 3.5 times, p=0.04]. Also, theEGR2expression level reduced significantly in all groups (p<0.02). The gene fold changes had no significant differences between the patients (p>0.8).Conclusions:We propose that the failure ofATF3gene expression improves the CE synthesis after sdLDL influx. Furthermore, the reducedEGR2gene expression level in the sdLDL-treated groups may be a negative factor in cholesterol homeostasis.

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Gigantol Improves Cholesterol Metabolism and Progesterone Biosynthesis in MA-10 Leydig Cells

Current Issues in Molecular Biology ◽

10.3390/cimb44010006 ◽

2021 ◽

Vol 44 (1) ◽

pp. 73-93

Author(s):

Audrey Basque ◽

Ha Tuyen Nguyen ◽

Mohamed Touaibia ◽

Luc J. Martin

Keyword(s):

Gene Expression ◽

Ferulic Acid ◽

Leydig Cells ◽

Cholesterol Metabolism ◽

Biological Activities ◽

Cholesterol Biosynthesis ◽

Male Hypogonadism ◽

Star Protein ◽

Progesterone Production ◽

Isoferulic Acid

In aging males, androgen production by testicular Leydig cells decreases at a rate of approximately 1% per year. Phenolic compounds may enhance testosterone biosynthesis and delay the onset of male hypogonadism. Gigantol is a bibenzyl compound isolated from several types of orchids of the genus Dendrobium. This compound has various biological activities, including antioxidant activity. However, its capacity to regulate gene expression and steroid production in testicular Leydig cells has never been evaluated. We investigated the effect of gigantol on MA-10 Leydig cells’ gene expression using an RNA-Seq approach. To further investigate the structure-function relationship of the hydroxy-methoxyphenyl moiety of gigantol, experiments were also performed with ferulic acid and isoferulic acid. According to transcriptomic analysis, all genes coding for cholesterol biosynthesis-related enzymes are increased in response to gigantol treatment, resulting in increased lipid droplets accumulation. Moreover, treatments with 10 μM gigantol increased StAR protein levels and progesterone production from MA-10 Leydig cells. However, neither ferulic acid nor isoferulic acid influenced StAR protein synthesis and progesterone production in MA-10 Leydig cells. Thus, our findings indicate that gigantol improves cholesterol and steroid biosynthesis within testicular Leydig cells.

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Transcriptome Analyses Revealed Adaptive-Responses in Livers of Mice Treated With Hua-Feng-Dan and Its “Guide Drug” Yaomu

10.21203/rs.3.rs-143356/v1 ◽

2021 ◽

Author(s):

Jia-Jia Liu ◽

Ya Zhang ◽

Shang-Fu Xu ◽

Feng Zhang ◽

Jing-Shan Shi ◽

...

Keyword(s):

Gene Expression ◽

Liver Toxicity ◽

Cholesterol Metabolism ◽

Enrichment Analysis ◽

Stroke Recovery ◽

Pathway Enrichment Analysis ◽

High Dose ◽

Hepatic Gene Expression ◽

Rna Seq ◽

Adaptive Responses

Abstract BackgroundHua-Feng-Dan is a patent Chinese medicine for stroke recovery and is effective against Parkinson’s disease models with modulatory effects on gut microbiota, but its effects on hepatic gene expression are unknown. This study used RNA-Seq to profile hepatic gene expression by Hua-Feng-Dan and its “Guide Drug” Yaomu.MethodsMice received orally Hua-Feng-Dan 1.2 g/kg, Yaomu 0.1-0.3 g/kg, or vehicle for 7 days. Liver pathology was examined, and total RNA was isolated for RNA-Seq. The bioinformatics, including GO and KEGG pathway enrichment analysis, two-dimensional clustering, Ingenuity Pathways Analysis (IPA), and Illumina BaseSpace Correlation Engine were used to analyze differentially expressed genes (DEGs). qPCR was performed to verify selected genes.ResultsHua-Feng-Dan and Yaomu did not produce liver toxicity as evidenced by histopathology and serum ALT and AST. GO Enrichment revealed Hua-Feng-Dan affected lipid homeostasis, protein folding and cell adhesion. KEGG showed activated cholesterol metabolism, bile secretion and PPAR signaling pathways. DEGs were identified by DESeq2 with p < 0.05 compared to controls. Hua-Feng-Dan produced 806 DEGs, Yaomu-0.1 had 235, and Yaomu-0.3 had 92 DEGs. qPCR on selected genes largely verified RNA-Seq results. IPA upstream regulator analysis revealed activation of MAPK and adaptive responses. Yaomu-0.1 had similar effects, but Yaomu-0.3 had little effects. Hua-Feng-Dan-induced DEGs were highly correlated with the GEO database of chemical-induced adaptive transcriptome changes in the liver. ConclusionHua-Feng-Dan at clinical dose did not produce liver pathological changes but induced metabolic and signaling pathway activations. Low dose of its Guide Drug Yaomu produced similar changes to a lesser extent, but high dose of Yaomu had little effects. The effects of Hua-Feng-Dan on liver transcriptome changes may produce adaptive responses to program the liver to produce beneficial or detrimental (over-dosed) pharmacological effects.

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