scholarly journals Perfluorooctanoic acid activates multiple nuclear receptor pathways and skews expression of genes regulating cholesterol homeostasis in liver of humanized PPARα mice fed an American diet

2020 ◽  
Vol 405 ◽  
pp. 115204 ◽  
Author(s):  
J.J. Schlezinger ◽  
H. Puckett ◽  
J. Oliver ◽  
G. Nielsen ◽  
W. Heiger-Bernays ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Perfluorooctanoic Acid ◽  
Cholesterol Homeostasis ◽  
Expression Of Genes

scholarly journals Oxysterol Nuclear Receptor LXRβ Regulates Cholesterol Homeostasis and Contractile Function in Mouse Uterus

2006 ◽  
Vol 282 (7) ◽  
pp. 4693-4701 ◽  
Author(s):  
Kevin Mouzat ◽  
Magali Prod'Homme ◽  
David H. Volle ◽  
Benoit Sion ◽  
Pierre Déchelotte ◽  
...  
Keyword(s):  
Cholesteryl Ester ◽  
Nuclear Receptor ◽  
Target Genes ◽  
Contractile Function ◽  
Contractile Activity ◽  
Critical Role ◽  
Cholesterol Homeostasis ◽  
Protective Mechanism ◽  
Mouse Uterus ◽  
Expression Of Genes

The uterus is an organ where lipid distribution plays a critical role for its function. Here we show that nuclear receptor for oxysterols LXRβ prevents accumulation of cholesteryl esters in mouse myometrium by controlling expression of genes involved in cholesterol efflux and storage (abca1 and abcg1). Upon treatment with an LXR agonist that mimics activation by oxysterols, expression of these target genes was increased in wild-type mice, whereas under basal conditions, lxrα;β-/- mice exhibited a marked decrease in abcg1 accumulation. This change resulted in a phenotype of cholesteryl ester accumulation. Besides, a defect of contractile activity induced by oxytocin or PGF2α was observed in mice lacking LXRβ. These results imply that LXRβ provides a safety valve to limit cholesteryl ester levels as a basal protective mechanism in the uterus against cholesterol accumulation and is necessary for a correct induction of contractions.

scholarly journals Perfluorooctanoic acid activates multiple nuclear receptor pathways and skews expression of genes regulating cholesterol homeostasis in liver of humanized PPARα mice fed an American diet

2020 ◽  
Author(s):  
JJ Schlezinger ◽  
H Puckett ◽  
J Oliver ◽  
G Nielsen ◽  
W Heiger-Bernays ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drinking Water ◽  
Constitutive Androstane Receptor ◽  
Density Lipoprotein ◽  
Perfluorooctanoic Acid ◽  
Consumer Products ◽  
Cholesterol Homeostasis ◽  
Dependent Manner ◽  
Independent Manner ◽  
Expression Of Genes

AbstractHumans are exposed to per- and polyfluoroalkyl substances (PFAS) in their drinking water, food, air, dust in their homes, and by direct use of consumer products. Increased concentrations of serum total cholesterol and low density lipoprotein cholesterol are among the endpoints best supported by epidemiology. The objectives of this study were to generate a new model for examining PFAS-induced dyslipidemia and to conduct molecular studies to better define mechanism(s) of action. We tested the hypothesis that PFOA exposure at a human-relevant level dysregulates expression of genes controlling cholesterol homeostasis in livers of mice expressing human PPARα (hPPARα). Female and male hPPARα and PPARα null mice were fed a diet based on the “What we eat in America” analysis and exposed to perfluorooctanoic acid (PFOA) in drinking water (8 µM) for 6 weeks. This resulted in a serum PFOA concentration of 48 μg/ml. PFOA increased liver mass, which was associated with histologically-evident lipid accumulation. PFOA induced PPARα and constitutive androstane receptor target gene expression in liver. Expression of genes in four pathways regulating cholesterol homeostasis were also measured. PFOA decreased expression of Hmgcr in a PPARα-dependent manner. PFOA decreased expression of Ldlr and Cyp7a1 in a PPARα-independent manner. Apob expression was not changed. Gene expression in females appeared to be more sensitive to PFOA exposure than in males. This novel study design (hPPARα mice, American diet, long term exposure) generated new insight on the effects of PFOA on cholesterol regulation in the liver and the role of hPPARα.

scholarly journals Persistent Neuroadaptations in the Expression of Genes Involved in Cholesterol Homeostasis Induced by Chronic, Voluntary Alcohol Intake in Rats

2018 ◽  
Vol 11 ◽  
Author(s):  
Josette Alsebaaly ◽  
Emilie Dugast ◽  
Laure Favot ◽  
Lydia Rabbaa Khabbaz ◽  
Marcello Solinas ◽  
...  
Keyword(s):  
Alcohol Intake ◽  
Cholesterol Homeostasis ◽  
Expression Of Genes

scholarly journals Effect of dietary eicosapentaenoic and docosahexaenoic acid on expression of rat liver genes controlling cholesterol homeostasis and on plasma cholesterol level

2014 ◽  
Vol 59 (No. 9) ◽  
pp. 391-398 ◽  
Author(s):  
T. Komprda ◽  
G. Zorníková ◽  
A. Knoll ◽  
Z. Vykoukalová ◽  
V. Rozíková ◽  
...  
Keyword(s):  
Docosahexaenoic Acid ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Homeostasis ◽  
Ldlr Gene ◽  
Expression Of Genes ◽  
Density Lipoprotein Receptor ◽  
Lower Plasma Cholesterol ◽  
Coa Reductase

A hypothesis that eicosapentaenoic acid + docosahexaenoic acid (EPA+DHA) lower plasma cholesterol via increased expression of the Insig-1 gene with ensuing decrease of expression of genes coding for 3-hydroxy-3-methyl-glutaryl-CoA reductase (Hmgcr) and low density lipoprotein receptor (Ldlr) was tested in rats fed a diet with 3% of fish oil (FO). Expression of the Insig-1 gene in the liver of the FO-fed rats was 730% (P < 0.05) of the control. However, contrary to the hypothesis, expression of the Hmgcr gene and Ldlr gene was 165% and 210% of the control (P > 0.05). Nevertheless, FO in the diet decreased (P < 0.05) plasma cholesterol of rats by 10% (from 1.19 to 1.07 mmol/l); it was therefore concluded that the cholesterol-lowering effect of EPA+DHA is at least partly based on mechanisms other than tested in the present experiment.  

scholarly journals MicroRNAs as Potential Biomarkers in Atherosclerosis

2019 ◽  
Vol 20 (22) ◽  
pp. 5547 ◽  
Author(s):  
Alexey Churov ◽  
Volha Summerhill ◽  
Andrey Grechko ◽  
Varvara Orekhova ◽  
Alexander Orekhov
Keyword(s):  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Inflammatory Cells ◽  
Cellular Protein ◽  
Cholesterol Homeostasis ◽  
Transcriptional Level ◽  
High Morbidity ◽  
Industrialized Countries ◽  
Rna Molecules ◽  
Expression Of Genes

Atherosclerosis is a complex multifactorial disease that, despite advances in lifestyle management and drug therapy, remains to be the major cause of high morbidity and mortality rates from cardiovascular diseases (CVDs) in industrialized countries. Therefore, there is a great need in reliable diagnostic/prognostic biomarkers and effective treatment alternatives to reduce its burden. It was established that microRNAs (miRNAs/miRs), a class of non-coding single-stranded RNA molecules, can regulate the expression of genes at the post-transcriptional level and, accordingly, coordinate the cellular protein expression. Thus, they are involved not only in cell-specific physiological functions but also in the cellular and molecular mechanisms of human pathologies, including atherosclerosis. MiRNAs may be significant in the dysregulation that affects endothelial integrity, the function of vascular smooth muscle and inflammatory cells, and cellular cholesterol homeostasis that drives the initiation and growth of an atherosclerotic plaque. Besides, distinct expression patterns of several miRNAs are attributed to atherosclerotic and cardiovascular patients. In this article, the evidence indicating the multiple critical roles of miRNAs and their relevant molecular mechanisms related to atherosclerosis development and progression was reviewed. Moreover, the effects of miRNAs on atherosclerosis enabled to exploit them as novel diagnostic biomarkers and therapeutic targets that may lead to better management of atherosclerosis and CVDs.

Activation of nuclear receptor CAR by an environmental pollutant perfluorooctanoic acid

2016 ◽  
Vol 91 (6) ◽  
pp. 2365-2374 ◽  
Author(s):  
Taiki Abe ◽  
Mirei Takahashi ◽  
Makoto Kano ◽  
Yuto Amaike ◽  
Chizuru Ishii ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Perfluorooctanoic Acid ◽  
Environmental Pollutant

scholarly journals Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Li Zhang ◽  
Prashant Rajbhandari ◽  
Christina Priest ◽  
Jaspreet Sandhu ◽  
Xiaohui Wu ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Plasma Cholesterol ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
High Cholesterol Diet ◽  
High Cholesterol ◽  
Cholesterol Levels ◽  
Expression Of Genes ◽  
Lysine Residues ◽  
Genetic Deletion

Cholesterol homeostasis is maintained through concerted action of the SREBPs and LXRs. Here, we report that RNF145, a previously uncharacterized ER membrane ubiquitin ligase, participates in crosstalk between these critical signaling pathways. RNF145 expression is induced in response to LXR activation and high-cholesterol diet feeding. Transduction of RNF145 into mouse liver inhibits the expression of genes involved in cholesterol biosynthesis and reduces plasma cholesterol levels. Conversely, acute suppression of RNF145 via shRNA-mediated knockdown, or chronic inactivation of RNF145 by genetic deletion, potentiates the expression of cholesterol biosynthetic genes and increases cholesterol levels both in liver and plasma. Mechanistic studies show that RNF145 triggers ubiquitination of SCAP on lysine residues within a cytoplasmic loop essential for COPII binding, potentially inhibiting its transport to Golgi and subsequent processing of SREBP-2. These findings define an additional mechanism linking hepatic sterol levels to the reciprocal actions of the SREBP-2 and LXR pathways.

scholarly journals Adrenocorticotropic Hormone Regulates the Activities of the Orphan Nuclear Receptor Nur77 through Modulation of Phosphorylation*

Endocrinology ◽  
1997 ◽  
Vol 138 (10) ◽  
pp. 4138-4146 ◽  
Author(s):  
Yanzhuang Li ◽  
Lester F. Lau
Keyword(s):  
Dna Binding ◽  
Nuclear Receptor ◽  
Binding Domain ◽  
Mitogen Activated Protein Kinase ◽  
Dna Binding Domain ◽  
Orphan Nuclear Receptor ◽  
Expression Of Genes ◽  
Acth Treatment ◽  
Mitogen Activated Protein

Abstract ACTH treatment of Y1 adrenocortical cells induces the synthesis of Nur77, an orphan nuclear receptor that can act as a potent trans-activator for such genes as 21-hydroxylase (CYP21). Nur77 has thus been proposed to be a mediator of ACTH action in activating the expression of genes that encode steroidogenic enzymes. Here we show that ACTH regulates the activity of Nur77 at the level of phosphorylation. ACTH induces the synthesis of transcriptionally active, DNA-binding Nur77 that is unphosphorylated at Ser354, which resides within the DNA-binding domain. By contrast, the Nur77 population that is constitutively present in Y1 cells is phosphorylated at Ser354 and does not bind DNA. Substitutions of Ser354 with negatively charged amino acids, such as Asp or Glu, dramatically decreased Nur77 DNA-binding and trans-activation activities, whereas mutation to the neutral Ala had no effect. Aside from phosphorylation within the DNA-binding domain, ACTH treatment does not induce modifications in the N- and C-terminal domains of Nur77 that significantly affect activity. Although the specific kinases that phosphorylate Nur77 in vivo are not known, the mitogen-activated protein kinase/pp90RSK pathway is not critical to Nur77 regulation. We propose that ACTH treatment of Y1 cells results in modulation of the activities of both kinases and phosphatases, which, in turn, regulate the activities of such transcription factors as Nur77.

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